Aromatic heterocyclic compound

ABSTRACT

The compound represented by the general formula: wherein ring A is benzene which may be substituted and the like; ring B is benzene which may be substituted and the like; X is a single bond and the like; Y is alkyl which may be substituted and the like; Z is CR 1  or nitrogen atom; R 1  is hydrogen and the like; R 2  is alkyl which may be substituted and the like or a pharmaceutically acceptable salt thereof is useful as a prevention/treatment agent of obesity, diabetes, and the like.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Phase of PCT International ApplicationNo. PCT/JP2013/066431, filed on Jun. 14, 2013, which claims priorityunder 35 U.S.C. 119(e) to U.S. Provisional Application No. 61/660,129,filed on Jun. 15, 2012, and to U.S. Provisional Application No.61/660,137, filed on Jun. 15, 2012, all of which are hereby expresslyincorporated by reference into the present application.

TECHNICAL FIELD

The present invention relates to an aromatic heterocyclic compound or apharmaceutically acceptable salt thereof having an acylcoenzyme A:diacylglycerolacyltransferase (DGAT) 1 inhibitory activity.

BACKGROUND ART

Obesity is a condition wherein fat is excessively accumulated in a body(Non-Patent Document 1), and may lead to hyperlipidemia,hypertriglycemia, lipid metabolism disorder, fatty liver, diabetes,hypertension, arteriosclerosis, cerebrovascular disorder, coronaryartery disease, dyspnoea, lumbago, gonarthrosis, and the like. Amongobesity, those having these diseases or those which may possibly causethese diseases in the future are defined as adiposity, and regarded asone of diseases.

DGAT is an enzyme catalyzing a reaction from diacylglyerol to TG, whichreaction is the final stage of triacylglycerol (TG) synthesis, and it isknown that DGAT has two kinds of subtypes, DGAT1 and DGAT2. Among these,DGAT1 is known to exist in liver, skeletal muscle, adipocytes, and thelike, and is involved in the TG synthesis in each tissue (Non-PatentDocument 2).

Further, when TG is absorbed in the small intestine, TG is decomposed bypancreatic lipase in the lumen of the small intestine to fatty acid andmono acylglycerol, then incorporated into small intestinal epithelialcells, and absorbed after it is resynthesized to TG in the epithelialcells, and it has been known that DGAT1 is also involved in the finalstage of TG resynthesis in the small intestinal epithelial cells(Non-Patent Document 3).

Therefore, a compound which inhibits DGAT1 is expected to improve thepathology of obesity since it not only inhibits TG synthesis inadipocyte, liver and the like by inhibiting the final step of TGsynthesis but also suppresses the TG absorption in small intestines bysuppressing the TG resynthesis in small intestine (Non-Patent Document4).

Further, a theory that the accumulation of TG in liver, skeletal muscle,and the like (ectopic fat accumulation) is a cause of insulin resistancein type 2 diabetes mellitus accompanying obesity has been widelyaccepted, and a compound which inhibits DGAT1 is expected to improve theinsulin sensitivity and has the therapeutic effect on type 2 diabetesmellitus by alleviating the ectopic fat accumulation (Non-PatentDocument 4). Furthermore, in a mouse deleted in DGAT1 by geneticmanipulation (DGAT1 knockout mouse), it was reported that theimprovement in the insulin sensitivity was observed as compared with awild type mouse (Non-Patent Document 5). It was recently reported that acompound which inhibits DGAT1 stimulates the action of glucagon-likepeptide-1 (GLP-1) and a protein which causes anorexia (Non-PatentDocument 6).

As a compound having a continuous aromatic ring structure, the followinghas been known. For example, in Patent Document 1,(2S)-2-[4′-(1-benzyl-1H-benzimidazole-2-yl)-biphenyl-4-yloxy]-3-phenyl-propionicacid (Example 70) and the like are disclosed as a compound whichinhibits protein-tyrosine phosphatase (PTPases) and is useful for thetreatment of insulin resistance accompanying obesity, glucoseintolerance, diabetes, hypertension, or ischemic disease.

In Patent Document 2, as a compound having an inhibitory activityagainst protein-tyrosine phosphatase 1B (PTP-1B) which is useful for thetreatment of type 2 diabetes mellitus,2-benzyl-4-[4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-yl]-4-oxo-butyricacid (Example 1),({4′-(3-benzylamino)imidazo[1,2-a]pyridin-2-yl)biphenyl-4-yl}oxy)(phenyl)aceticacid, {[4′-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]oxy}(phenyl) aceticacid (Example 3), and the like are disclosed.

In Patent Document 3, Patent Document 4 and Patent Document 5, acompound having an inhibitory activity against Factor VIIa, Factor IXa,Factor Xa, and/or Factor XIa which has a structure wherein biphenyl andnitrogen-containing fused heterocyclic ring are bonded is disclosed.However, the chemical structure is restricted to those having astructure wherein the nitrogen-containing fused heterocyclic ring isbonded at the 3-position of the biphenyl.

In Patent Document 6,2-[[2′-(5-phenyl-1H-imidazol-2-yl)[1,1′-biphenyl]-3-yl]oxy]acetic acid(Example 46) and the like as a compound having the therapeutic effect onobesity and diabetes by inhibiting adipocyte fatty acid-binding protein(aP2) are disclosed.

In Non-Patent Document 7, 2-[[2′-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)[1,1′-biphenyl]-3-yl]oxy]acetic acid,2-[[2′-(4,5-diphenyl-1H-imidazol-2-yl)[1,1′-biphenyl]-3-yl]oxy]aceticacid, and the like as a compound which binds to adipocyte fattyacid-binding protein (aFABP) are reported.

As another compound having a continuous ring structure, those in, forexample, Patent Documents 7 to 14 and Non-Patent Document 8 are known.

Also, as a compound having DGAT1 inhibitory activity, for example,heteroarylbenzene derivatives (Patent Document 15), bicyclicheterocyclic compounds (Patent Document 16), triazolopyridinederivatives (Patent Document 17), imidazole derivatives (PatentDocuments 18 to 20), spiro-ring compounds (Patent Document 21), andbiaryl compounds (Patent Document 22) are known.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: WO99/58518A-   Patent Document 2: WO2004/99168A-   Patent Document 3: WO2003/6670A-   Patent Document 4: WO2003/6011A-   Patent Document 5: US2003/0114457A-   Patent Document 6: WO00/59506A-   Patent Document 7: WO2006/034440-   Patent Document 8: WO2011/002067-   Patent Document 9: JP1994/116251-   Patent Document 10: WO2003/093248-   Patent Document 11: WO2000/066578-   Patent Document 12: WO2009/079593-   Patent Document 13: WO1995/015594-   Patent Document 14: WO2003/064410-   Patent Document 15: WO2009/011285-   Patent Document 16: WO2010/107765-   Patent Document 17: WO2009/126861-   Patent Document 18: WO2012/015693-   Patent Document 19: WO2012/047772-   Patent Document 20: WO2012/044567-   Patent Document 21: WO2012/009217-   Patent Document 22: WO2008/067257

Non-Patent Documents

-   Non-Patent Document 1: Nanzando's Medical Dictionary (19^(th)    Edition), page 2113, 2006-   Non-Patent Document 2: Proc. Natl. Acad. Sci. USA, Vol. 95, page    13018, 1998-   Non-Patent Document 3: J. Biol. Chem. Vol. 278, page 18532, 2003-   Non-Patent Document 4: Arterioscler. Thromb. Vasc. Biol. Vol. 25,    page 482, 2005-   Non-Patent Document 5: The Journal of Clinical Investigation, 109(8)    1049-1055 (2002)-   Non-Patent Document 6: American Chemical Society National Meeting    Abst. MEDI 315 (2010)-   Non-Patent Document 7: Bioorganic & Medicinal Chemistry Letters    17(12) 3511-3515, 2007-   Non-Patent Document 8: J. Med. Chem. 50(13), 3086-3100 (2007)

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide an aromaticheterocyclic compound or a pharmaceutically acceptable salt thereofhaving DGAT1 inhibitory activity, and a DGAT1 inhibitor which is usefulfor the prevention and/or treatment of obesity, or hyperlipidemia,hypertriglyceridemia, lipid metabolism disorder, fatty liver,hypertension, arteriosclerosis, diabetes, and the like caused byobesity.

Means to Solve the Problems

As a result that the inventors of present invention have conductedearnest studies to solve the aforementioned problems, and as a resultthey have found the aromatic heterocyclic compound or a pharmaceuticallyacceptable salt thereof represented by a formula as below has anexcellent DGAT1 inhibitory activity and accomplished the presentinvention.

Namely, the present invention is as follows:

1. A compound represented by the general formula (1):

[wherein ring A is benzene which may be substituted or 6-memberedmonocyclic aromatic heterocycle which may be substituted;

ring B is benzene which may be substituted or 6-membered monocyclicaromatic heterocycle which may be substituted;

X is a single bond or —O—;

Y is alkyl which may be substituted or cycloalkyl which may besubstituted;

Z is CR¹ or nitrogen atom;

R¹ is hydrogen, halogen atom, alkoxy, or alkyl which may be substituted;

(i) when Z is CR¹, R² is the formula as below:

{wherein Z′ represents a single bond, alkylene, -Alk-O—, or-Alk¹-O-Alk²-,(wherein Alk, Alk¹, and Alk² each independently represent alkylene, andthe bond at the right end represents a bond to ring C),

ring C represents an aromatic hydrocarbon group or an aromaticheterocyclic group},

R³ and R⁴ each independently represent hydrogen, halogen atom, alkylwhich may be substituted, alkoxy which may be substituted, alkylsubstituted with non-aromatic heterocycle, or carbonyl substituted withnon-aromatic heterocycle); (ii) when Z is nitrogen atom, R² is alkylwhich may be substituted, alkoxy which may be substituted, alkylthio, anaromatic hydrocarbon group which may be substituted, a non-aromaticheterocyclic group which may be substituted, cycloalkyl which may besubstituted, aryloxy which may be substituted, heteroaryloxy which maybe substituted, cycloalkyloxy, or cycloalkylalkoxy],

or a pharmaceutically acceptable salt thereof.

2. The compound according to the above 1, wherein the compound isrepresented by the general formula (1-A):

[wherein ring A is benzene which may be substituted or 6-memberedmonocyclic aromatic heterocycle which may be substituted;

ring B¹ is benzene which may be substituted or 6-membered monocyclicaromatic heterocycle which may be substituted;

R¹ is hydrogen, halogen atom, alkoxy, or alkyl which may be substituted;

R^(2a) is the formula as below:

{wherein Z′ represents a single bond, alkylene, -Alk-O—, or-Alk¹-O-Alk²-,(wherein Alk, Alk¹, and Alk² each independently represent alkylene, andthe bond at the right end represents a bond to ring C),

ring C represents an aromatic hydrocarbon group or an aromaticheterocyclic group,

R³ and R⁴ each independently represent hydrogen, halogen atom, alkylwhich may be substituted, alkoxy which may be substituted, alkylsubstituted with non-aromatic heterocycle, or carbonyl substituted withnon-aromatic heterocycle};

X is a single bond or —O—;

Y^(a) is alkyl which may be substituted or cycloalkyl which may besubstituted];

or a pharmaceutically acceptable salt thereof.

3. The compound according to the above 2 wherein ring A is benzene whichmay be substituted or pyridine which may be substituted, or apharmaceutically acceptable salt thereof.

4. The compound according to the above 2 or 3 wherein ring B¹ is benzenewhich may be substituted, pyridine which may be substituted, orpyrimidine which may be substituted, or a pharmaceutically acceptablesalt thereof.

5. The compound according to any one of the above 2 to 4 wherein X is—O—; and Y^(a) is alkyl substituted with carboxy, or a pharmaceuticallyacceptable salt thereof.

6. The compound according to the above 2 which is selected from

-   1-{[(5′-fluoro-4-methyl-6′-{5-[2-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}-3,3′-bipyridin-6-yl)oxy]methyl}cyclopropanecarboxylic    acid,-   2,2-dimethyl-3-{[4-methyl-5-(2-{5-[2-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}-pyrimidin-5-yl)pyridin-2-yl]oxy}propanoic    acid,-   3-{[5′-fluoro-4-methyl-6′-(5-phenyl-1H-imidazol-2-yl)-3,3′-bipyridin-6-yl]oxy}-2,2-dimethylpropanoic    acid,-   2-ethyl-2-[({5-[6-(5-phenyl-1H-imidazol-2-yl)pyridin-3-yl]pyrazin-2-yl}oxy)methyl]-butanoic    acid,-   3-[4-(5-{5-[4-(difluoromethoxy)phenyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy]-2,2-dimethylpropanoic    acid,-   2,2-dimethyl-3-[4-(5-{5-[2-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}pyridin-2-yl)-phenoxy]propanoic    acid,-   2,2-dimethyl-3-(4-{5-[5-(2-phenoxyethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-propanoic    acid,-   2,2-dimethyl-3-({4-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)pyrimidin-5-yl]pyridin-2-yl}oxy)propanoic    acid,-   2,2-dimethyl-3-({4-methyl-5-[3-methyl-4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin-2-yl}oxy)propanoic    acid,-   2,2-dimethyl-3-({5-[3-methyl-4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin-2-yl}oxy)-propanoic    acid,-   3-(4-{5-[5-(2,4-difluorophenyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoic    acid,-   2-ethyl-2-[({4-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)pyrimidin-5-yl]pyridin-2-yl}-oxy)methyl]butanoic    acid,-   1-[({4-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)pyrimidin-5-yl]pyridin-2-yl}oxy)-methyl]cyclobutanecarboxylic    acid,-   2,2-dimethyl-3-({5-[4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin-2-yl}oxy)propanoic    acid,-   3-[(5-{4-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid,-   1-({[5′-fluoro-4-methyl-6′-(5-phenyl-1H-imidazol-2-yl)-3,3′-bipyridin-6-yl]oxy}-methyl)cyclopropanecarboxylic    acid,-   3-[(5-{3-cyano-4-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid,-   2,2-dimethyl-3-[4-(5-{5-[2-(trifluoromethyl)benzyl]-1H-imidazol-2-yl}pyridin-2-yl)-phenoxy]propanoic    acid,-   3-(4-{5-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoic    acid,-   2,2-dimethyl-3-({4-methyl-5-[4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin-2-yl}oxy)-propanoic    acid,-   3-[4-(5-{5-[(benzyloxy)methyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy]-2,2-dimethylpropanoic    acid,-   3-{4-[5-(4-chloro-5-phenyl-1H-imidazol-2-yl)pyridin-2-yl]phenoxy}-2,2-dimethylpropanoic    acid,-   2,2-dimethyl-3-(4-{5-[5-(thiophen-2-yl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-propanoic    acid,-   3-[(5-{4-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid, and-   2,2-dimethyl-3-{4-[5-(5-phenyl-1H-imidazol-2-yl)pyridin-2-yl]phenoxy}propanoic    acid,    or a pharmaceutically acceptable salt thereof.    7. The compound according to the above 1 wherein the compound is    represented by the general formula (1-B):

(wherein ring A represents benzene which may be substituted or6-membered monocyclic aromatic heterocycle which may be substituted;

ring B² represents benzene which may be substituted or 6-memberedmonocyclic aromatic heterocycle which may be substituted;

R^(2b) represents alkyl which may be substituted, alkoxy which may besubstituted, alkylthio, an aromatic hydrocarbon group which may besubstituted, a non-aromatic heterocyclic group which may be substituted,cycloalkyl which may be substituted, aryloxy which may be substituted,heteroaryloxy which may be substituted, cycloalkyloxy, orcycloalkylalkoxy,

X represents a single bond or —O—;

Y^(b) represents alkyl which may be substituted or cycloalkyl which maybe substituted);

or a pharmaceutically acceptable salt thereof.

8. The compound according to the above 7 wherein ring A is benzene whichmay be substituted or pyridine which may be substituted, or apharmaceutically acceptable salt thereof.

9. The compound according to the above 7 or 8 wherein ring B² is benzenewhich may be substituted, pyridine which may be substituted orpyrimidine which may be substituted, or a pharmaceutically acceptablesalt thereof.

10. The compound according to any one of the above 7 to 9 wherein R^(2b)is alkyl which may be substituted, alkoxy which may be substituted, anaromatic hydrocarbon group which may be substituted, or aryloxy whichmay be substituted, or a pharmaceutically acceptable salt thereof.11. The compound according to any one of the above 7 to 10 wherein X is—O—, and Y^(b) is alkyl which may be substituted with carboxy, or apharmaceutically acceptable salt thereof.12. The compound according to the above 7 which is selected from

-   2,2-dimethyl-3-[(5-{4-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]phenyl}-pyridin-2-yl)oxy]propanoic    acid,-   3-[(5-{3-fluoro-4-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid,-   2,2-dimethyl-3-({4′-methyl-5-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]-2,3′-bipyridin-6′-yl}oxy)propanoic    acid,-   3-[(5-{4-[3-(4-fluorophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid,-   3-[(5-{4-[3-(4-cyanophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid,-   2,2-dimethyl-3-[(5-{4-[3-(2,2,3,3,3-pentafluoropropoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)oxy]propanoic    acid sodium salt,-   (trans-4-{4′-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]biphenyl-4-yl}cyclohexyl)acetic    acid,-   (trans-4-{4-{5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyridin-2-yl}phenyl)-cyclohexyl]acetic    acid,-   [4-(5-{4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)cyclohexyl]-acetic    acid,-   2,2-dimethyl-3-({5-[4-(5-phenyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-2-yl}oxy]-propanoic    acid,-   (4-{5-[4-(3-ethoxy-1H-1,2,4-triazol-5-yl)phenyl]pyridin-2-yl}cyclohexyl)acetic    acid,-   3-({5-[4-(3-ethoxy-1H-1,2,4-triazol-5-yl)phenyl]-4-methylpyridin-2-yl}oxy)-2,2-dimethylpropanoic    acid,-   2,2-dimethyl-3-({4-methyl-6′-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]-3,3′-bipyridin-6-yl}oxy)propanoic    acid,-   3-[(5-{4-[3-(2,4-difluorophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid, and-   3-[(5-{3-fluoro-4-[3-(4-fluorophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic    acid,    or a pharmaceutically acceptable salt thereof.    13. A diacylglycerol acyltransferase (DGAT) 1 inhibitor comprising    the compound according to any one of the above 1 to 12 or a    pharmaceutically acceptable salt thereof as active ingredient.    14. The DGAT 1 inhibitor according to the above 13 which is a    prophylactic or treatment agent of obesity.    15. The DGAT 1 inhibitor according to the above 13 which is a    prophylactic or treatment agent of hyperlipidemia,    hypertriglyceridemia, lipid metabolism disorder or fatty liver.    16. The DGAT 1 inhibitor according to the above 13 wherein the agent    is a prevention/treatment agent of type 2 diabetes mellitus,    diabetic complication (including diabetic peripheral neuropathy,    diabetic nephropathy, diabetic retinopathy and diabetic    macroangiopathy), arteriosclerosis, hypertension, cerebrovascular    disorder, coronary artery disease, dyspnoea, lumbago or    gonarthrosis.    17. The DGAT 1 inhibitor according to the above 13 wherein the agent    is a prevention/treatment agent of type 2 diabetes mellitus or    diabetic complication.    18. The DGAT 1 inhibitor according to the above 13 wherein the agent    is a prevention/treatment agent of familial hyperchylomicronemia.    19. Use of the compound according to any one of the above 1 to 12 or    a pharmaceutically acceptable salt thereof for the    prevention/treatment of hyperlipidemia, hypertriglyceridemia, lipid    metabolism disorder, fatty liver, type 2 diabetes mellitus, diabetic    complication (including diabetic peripheral neuropathy, diabetic    nephropathy, diabetic retinopathy and diabetic macroangiopathy),    arteriosclerosis, hypertension, cerebrovascular disorder, coronary    artery disease, dyspnoea, lumbago or gonarthrosis.    20. Use of the compound according to any one of the above 1 to 12 or    a pharmaceutically acceptable salt thereof for the    prevention/treatment of familial hyperchylomicronemia.    21. A method for the prevention/treatment of hyperlipidemia,    hypertriglyceridemia, lipid metabolism disorder, fatty liver, type 2    diabetes mellitus, diabetic complication (including diabetic    peripheral neuropathy, diabetic nephropathy, diabetic retinopathy    and diabetic macroangiopathy), arteriosclerosis, hypertension,    cerebrovascular disorder, coronary artery disease, dyspnoea, lumbago    or gonarthrosis, characterized by administering the compound    according to any one of the above 1 to 12 or a pharmaceutically    acceptable salt thereof to a patient.    22. A method for the prevention/treatment of familial    hyperchylomicronemia, characterized by administering the compound    according to any one of the above 1 to 12 or a pharmaceutically    acceptable salt thereof to a patient.

Another aspect of the present invention includes a compound representedby the general formula (A) as below:

[wherein ring A represents benzene which may be substituted or6-membered monocyclic aromatic heterocycle which may be substituted;

ring B¹ represents benzene which may be substituted or 6-memberedmonocyclic aromatic heterocycle which may be substituted;

X^(A) represents a single bond or —O—;

Y^(A) represents:

(1) cycloalkyl which may be substituted with the group selected from (i)to (v) as below:

(i) carboxy,

(ii) carboxyalkyl

(iii) alkoxyalkyl

(iv) aminocarbonyl, and

(v) alkoxycarbonylalkyl, or

(2) alkyl which may be substituted with a group selected from (i) and(ii) as below:

(i) carboxy, and

(ii) aminocarbonyl which may be mono- or di-substituted with alkyl whichmay be substituted with 1 to 3 hydroxyls,

R^(1A) represents hydrogen, alkyl, or halogen atom; and

R^(2A) represents (1) alkyl which may be substituted with a groupselected from halogen atom, alkoxy, and hydroxy, (2) halogen atom, (3)cyano, (4) aminocarbonyl which may be mono- or di-substituted withalkyl, (5) alkoxycarbonyl, or (6) tetrahydropyranyl;

with the proviso that when R^(1A) is hydrogen atom; R^(2A) is alkylwhich may be substituted with halogen atom; ring A is:

(wherein a bond at the right end represents a bond to ring B, X₁represents N or CRX₁, X₂ represents N or CRX₂, X₃ represents N or CRX₃,X₄ represents N or CRX₄, RX₁, RX₂, RX₃ and RX₄ each represents hydrogen,straight or branched alkyl which may be substituted with halogen atom,alkyl having a cyclic structure which may be substituted with halogenatom, straight or branched alkoxy, halogen atom, or cyano),

then an aspect wherein Y^(A) is alkyl substituted with carboxy, andX^(A) is —O— is excluded,

or a pharmaceutically acceptable salt thereof.]

Another aspect of the present invention includes a compound representedby the general formula (B) as below:

(wherein ring B³ represents 6-membered monocyclic aromatic heterocyclewhich may be substituted;

P represents hydrogen or alkyl,

Q represents hydrogen, or a group which forms carbonyl together with P,

X^(B) represents a single bond or —CH₂CO— wherein a bond at the rightend represents a bond to piperazine,

Y^(B) represents:

(1) phenyl which may be substituted with a group selected from (i) to(vi) as below:

(i) halogen atom,

(ii) alkyl,

(iii) carboxyalkyl

(iv) hydroxyalkyl

(v) alkoxycarbonylalkyl which may be substituted with a group selectedfrom hydroxy, aralkyloxy, and 2,2-dimethyl-1,3-dioxolane, and

(vi) aminocarbonylalkyl which may be mono- or di-substituted with alkylwhich may be substituted with a group selected from hydroxy and2,2-dimethyl-1,3-dioxolane,

(2) pyridyl which may be substituted with alkyl, or

(3) alkyl which may be substituted with carboxy,

R^(1B) represents hydrogen or alkyl, and

R^(2B) represents cycloalkyl or alkyl which may be substituted withhalogen),

or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention also includes a compoundrepresented by the general formula (C) as below:

[wherein ring B¹ represents benzene which may be substituted or6-membered monocyclic aromatic heterocycle which may be substituted,

X^(C) represents a single bond, —O—, —OCH₂— (wherein a bond at the rightend represents a bond to piperazine, or alkylene),

Y^(C) represents:

(1) phenyl which may be substituted with a group selected from (i) to(v) as below:

(i) halogen atom,

(ii) alkyl,

(iii) carboxyalkyl

(iv) carboxy, and

(v) alkoxy, or

(2) alkyl which may be substituted with carboxy, and

R^(2C) represents alkyl which may be substituted with halogen],

or a pharmaceutically acceptable salt thereof.

Further, another aspect of the present invention includes a compoundrepresented by the general formula (D) as below:

[wherein ring B³ represents 6-membered monocyclic aromatic heterocyclicring which may be substituted,

X^(D) represents a single bond, —OCH₂— or —O— (wherein a bond at theright end represents a bond to cyclohexane),

Y^(D) represents:

(1) phenyl which may be substituted with a group selected from (i) to(iv) as below:

(i) halogen atom,

(ii) alkyl,

(iii) carboxyalkyl, and

(iv) carboxy

(2) pyridyl which may be substituted with carboxy, or

(3) alkyl which may be substituted with carboxy, and

R^(2D) represents alkyl which may be substituted with halogen],

or a pharmaceutically acceptable salt thereof.

The groups represented by each symbol in the present specification areexplained below. The abbreviations used in the present specificationeach have the meanings as below.

-   Ac: acetyl-   Bn: benzyl-   Boc: t-butoxycarbonyl-   EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et: ethyl-   HOBt: 1-hydroxybenzotriazole-   Me: methyl-   MOM: methoxymethyl-   Ph: phenyl-   SEM: 2-(trimethylsilyl)ethoxymethyl-   TBS: t-butyldimethylsilyl-   t-Bu: t-butyl-   Tf: trifluoromethanesulfonyl-   TFA: trifluoroacetic acid-   THF: tetrahydrofuran-   TMS: trimethylsilyl

As “halogen atom”, fluorine atom, chlorine atom, bromine atom, andiodine atom can be mentioned. Among them, fluorine atom and chlorineatom are preferred.

As “alkyl”, for example, straight or branched alkyl having 1 to 8 carbonatom, preferably 1 to 6 carbon atoms, can be mentioned, andspecifically, methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, 2-methylpropyl, 2-ethylbutyl, 2-propylpentyl,and the like can be mentioned.

As “cycloalkane”, for example, cycloalkane having 3 to 8 carbon atoms,preferably 3 to 6 carbon atoms, can be mentioned, and specifically,cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, andthe like can be mentioned.

As “cycloalkyl”, for example, cycloalkyl having 3 to 8 carbon atoms,preferably 3 to 6 carbon atom, can be mentioned, and specifically,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike can be mentioned.

As “alkoxy”, for example, straight or branched alkoxy having 1 to 8carbon atom, preferably 1 to 6 carbon atoms, can be mentioned, andspecifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,isobutoxy, pentyloxy, hexyloxy, and the like can be mentioned.

As “alkylene”, for example, straight or branched alkylene having 1 to 6carbon atom, preferably 1 to 3 carbon atoms, can be mentioned, andspecifically, methylene, ethylene, propylene, isopropylene, butylene,isobutylene, and the like can be mentioned.

As “alkoxycarbony”, for example, straight or branched alkoxycarbonylhaving 2 to 9 carbon atoms, can be mentioned, and specifically,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like can bementioned.

As “alkoxycarbonylalkyl”, for example, the above “alkyl” substitutedwith the above “alkoxycarbonyl” can be mentioned, and specifically,methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, and the like can be mentioned.

As “carboxyalkyl”, for example, the above “alkyl” substituted withcarboxy can be mentioned, and specifically, carboxymethyl, carboxyethyl,carboxypropyl, carboxyisopropyl, carboxy-t-butyl, carboxyhexyl, and thelike can be mentioned.

As “alkoxyalkyl”, for example, the above “alkyl” substituted with theabove “alkoxy” can be mentioned, and specifically, methoxymethyl,methoxyethyl, ethoxymethyl, ethoxyethyl, t-butoxymethyl, and the likecan be mentioned.

As “hydroxyalkyl”, for example, the above “alkyl” substituted withhydroxy can be mentioned, and specifically, hydroxymethyl,1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, andthe like can be mentioned.

As “aminocarbonylalkyl”, for example, the above “alkyl” substituted withaminocarbonyl can be mentioned, and specifically, aminocarbonylmethyl,aminocarbonylethyl, and the like can be mentioned.

As “aromatic hydrocarbon group”, for example, 6 to 14 memberedmonocyclic, bicyclic, or tricyclic aromatic hydrocarbon group can bementioned, specifically, phenyl, naphthyl, phenanthryl, anthryl, and thelike can be mentioned, and phenyl is particularly preferred.

As “aromatic heterocyclic group”, for example, 5 to 14 memberedmono-cyclic or bi-cyclic aromatic heterocyclic group containing 1 to 4heteroatoms selected from nitrogen atom, sulfur atom and oxygen atomother than carbon atom as an annular atom can be mentioned, andspecifically, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, azepinyl, diazepinyl,furyl, pyranyl, oxepinyl, thienyl, thiopyranyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, oxazinyl, oxadiazinyl,oxazepinyl, oxadiazepinyl, thiadiazolyl, thiazinyl, indolyl, isoindolyl,benzofuryl, benzothienyl, indazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, quinazolinyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, and the like can mentioned.

As “non-aromatic heterocyclic group”, for example, 5 to 14 memberedmono-cyclic or bi-cyclic non-aromatic heterocyclic group containing 1 to4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atomother than carbon atoms as an annular atom can be mentioned.Specifically, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, homopiperidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, imidazolinyl, tetrahydrofuryl,dihydrofuryl, tetrahydrothienyl, dihydrothienyl, tetrahydropyridyl,dihydrobenzofuryl, dihydrobenzothienyl, and the like can be mentioned.

As “alkylthio”, for example, straight or branched alkylthio having 1 to8 carbon atom, preferably 1 to 4 carbon atoms can be mentioned, andspecifically, methylthio, ethylthio, propylthio, butylthio, and the likecan be mentioned.

Aryl in “aryloxy” has the same meaning as in the above “aromatichydrocarbon group”, and phenyl is particularly preferred. As a specificexample for “aryloxy”, phenyloxy, naphthyloxy, and the like can bementioned.

Heteroaryl in “heteroaryloxy” has the same meaning as in the above“aromatic heterocyclic group”, and 5 to 6-membered monocyclic aromaticheterocyclic group containing 1 to 4 heteroatoms selected from nitrogenatom, sulfur atom and oxygen atom other than carbon atoms as an annularatom is particularly preferred. As a specific example for“heteroaryloxy”, pyridyloxy, pyrimidinyloxy, pyrazyloxy, and the likecan be mentioned.

As “cycloalkyloxy”, for example, cycloalkyloxy having 3 to 8 carbonatoms, preferably 3 to 6 carbon atoms can be mentioned, andspecifically, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy, and the like can be mentioned.

As “cycloalkylalkoxy”, the above “alkoxy” substituted with the above“cycloalkyl” can be mentioned, and specifically, cyclopropylmethoxy,cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy,cyclohexylmethoxy, cycloheptylmethoxy, and the like can be mentioned.

As “aralkyloxy”, for example, the above “alkoxy” substituted with theabove “aromatic hydrocarbon group” can be mentioned, and specifically,benzyloxy, phenethyloxy, 1-naphthylmethoxy, 2-naphthylmethoxy, and thelike can be mentioned.

As “aralkyloxycarbonyl”, for example, the above “alkoxycarbonyl”substituted with the above “aromatic hydrocarbon group” can bementioned, and specifically benzyloxycarbonyl, phenethyloxycarbonyl,1-naphthylmethoxycarbonyl, 2-naphthylmethoxycarbonyl, and the like canbe mentioned.

As “alkyl substituted with non-aromatic heterocycle”, for example, theabove “alkyl” substituted with the above “non-aromatic heterocyclicgroup” can be mentioned, and specifically, pyrrolidinomethyl,piperidinoethyl, morpholinomethyl, morpholinoethyl, piperidinomethyl,piperidinoethyl, and the like can be mentioned.

As “carbonyl substituted with non-aromatic heterocycle”, for example,carbonyl substituted with the above “non-aromatic heterocyclic group”can be mentioned, and specifically, piperidinocarbonyl,morpholinocarbonyl, piperidinocarbonyl, and the like can be mentioned.

As “6-membered monocyclic aromatic heterocyclic ring” in ring A, forexample, 6-membered monocyclic aromatic heterocyclic ring containing 1to 4 nitrogen atoms other than carbon atom as an annular atom can bementioned, and specifically, pyridine, pyrazine, pyrimidine, pyridazine,triazine, and tetrazine can be mentioned. Among them, 6-memberedmonocyclic aromatic heterocyclic ring containing 1 to 2 nitrogen atomsother than carbon atom as an annular atom can be preferably mentioned.Of these, pyridine, pyrazine, pyrimidine, and pyridazine are preferred,pyridine and pyrazine are more preferred, and pyridine is particularlypreferred.

As a substituent group of “benzene which may be substituted” and“6-membered monocyclic aromatic heterocycle which may be substituted” inRing A, for example, 1 to 3 alkyls can be mentioned, and when 2 or morealkyls are present, the substituent groups may be same or different. Asa particularly preferred substituent group, methyl can be mentioned.

As “6-membered monocyclic aromatic heterocycle” in ring B, B¹, B² andB³, for example, 6-membered monocyclic aromatic heterocycle containing 1to 4 nitrogen atoms other than carbon atom as an annular atom can bementioned, and specifically, pyridine, pyrazine, pyrimidine, pyridazine,triazine, and tetrazine can be mentioned. Among them, 6-memberedmonocyclic aromatic heterocycle containing 1 to 2 nitrogen atoms otherthan carbon atom as an annular atom can be preferably mentioned. Ofthese, pyridine, pyrazine, pyrimidine and pyridazine are preferred, andpyridine and pyrimidine are particularly preferred.

As a substituent group of “benzene which may be substituted” and“6-membered monocyclic aromatic heterocycle which may be substituted” inring B and ring B¹, for example, alkyl, halogen atom, and cyano can bementioned, and 1 to 3 of these substituent groups may be present. When 2or more substituent groups are present, the substituent groups may besame or different. As a particularly preferred substituent group,methyl, fluorine atom, chlorine atom, and cyano can be mentioned.

As a substituent group of “benzene which may be substituted” and“6-membered monocyclic aromatic heterocycle which may be substituted” inring B², for example, a group selected from halogen atom and cyano canbe mentioned. 1 to 3 of these substituent groups may be present, andwhen 2 or more substituent groups are present, the substituent groupsmay be same or different. As a particularly preferred substituent group,fluorine atom, chlorine atom, and cyano can be mentioned.

As a preferred embodiment of ring A-ring B, ring A-ring B¹, and ringA-ring B², groups represented by the formula as below can be mentioned:

(wherein G₁, G₂ and G₃ represents CH or nitrogen atom.)

As “aromatic heterocyclic group” in ring C, the above “aromaticheterocyclic group” can be mentioned, and 5 to 6-membered monocyclicaromatic heterocyclic group containing 1 to 3 heteroatoms selected fromnitrogen atom, sulfur atom and oxygen atom other than carbon atom as anannular atom can be preferably mentioned. Of these, pyridyl,pyrimidinyl, pyrazolyl, thienyl, isoxazolyl, oxazolyl, thiazolyl,oxadiazolyl, and triazolyl are preferred, pyridyl, pyrimidinyl, thienyl,thiazolyl, oxadiazolyl, and oxazolyl are more preferred, and thienyl isparticularly preferred.

As ring C, “aromatic hydrocarbon group” is preferred.

As “alkyl” in Y, Y^(a), Y^(b), Y^(A), Y^(B), Y^(C), and Y^(D), a groupwhich has 2 substituent groups (R⁵ and R⁶) on the same carbon atom ofalkyl, and wherein the 2 substituent groups forms a ring together withthe adjacent carbon atom is included. As such a group, for example, agroup represented by the formula as below can be mentioned:

(wherein Alk³ and Alk⁴ are same or different, and each representalkylene, n represents an integer from 0 to 1, and R⁵ and R⁶ eachrepresent hydrogen or alkyl, or R⁵ and R⁶ represent a group which formscycloalkane together with the adjacent carbon atom. Further, a bond atthe right end represents a bond to X, X^(A), X^(B), X^(C), and X^(D).)

As a preferred specific example of “alkyl” in Y, Y^(a), Y^(b), Y^(A),Y^(B), Y^(C), and Y^(D), following groups can be mentioned:

(wherein a bond at the right end represents a bond to X, X^(A), X^(B),X^(C), and X^(D).)

In particular, following groups are preferred:

(wherein a bond at the right end represents a bond to X, X^(A), X^(B),X^(C), and X^(D).)

As a substituent group of “alkyl which may be substituted” in Y andY^(a), for example, aminocarbonyl which may be substituted with alkylwhich may be substituted with 1 to 3 hydroxys, and carboxy can bementioned, and 1 to 3 of these substituent groups may be present. When 2or more substituent groups are present, the substituent groups may besame or different. Among these, as a preferred substituent group,carboxy can be mentioned.

As a substituent group of “alkyl which may be substituted” in Y^(b), forexample, carboxy can be mentioned.

As a substituent group of “cycloalkyl which may be substituted” inY^(a), for example, carboxyalkyl can be mentioned, and 1 to 3 of thesubstituent groups may be present. As a specific example of thesubstituent group, carboxymethyl and the like can be mentioned.

As a substituent group of “cycloalkyl which may be substituted” in Y andY^(b), for example, carboxyalkyl, carboxy, alkoxyalkyl, andaminocarbonyl can be mentioned, and 1 to 3 of these substituent groupsmay be present. When 2 or more substituent groups are present, thesubstituent groups may be same or different. As a preferred substituentgroup, carboxyalkyl, carboxy, and alkoxyalkyl can be mentioned.

As “cycloalkyl” in Y^(b), cycloalkyl containing 3 to 6 carbon atoms ispreferred, and in particular, cyclohexyl is preferred.

As Y^(b), “alkyl which may be substituted” is preferred.

As a substituent group of “alkyl which may be substituted” in R¹, forexample, 1 to 6 halogen atoms can be mentioned, and when 2 or moresubstituent groups are present, the substituent groups may be same ordifferent. As a particularly preferred substituent group, fluorine atomcan be mentioned. As a specific example of “alkyl which may besubstituted”, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,2,2,3,3,3-pentafluoropropyl, and the like can be mentioned, and inparticular, trifluoromethyl is preferred.

As “halogen atom” represented by R¹, chlorine atom is particularlypreferred.

As “alkyl” represented by R¹, alkyl containing 1 to 3 carbon atoms ispreferred, and in particular, methyl is preferred.

As “alkoxy” represented by R¹, alkoxy containing 1 to 3 carbon atoms ispreferred, and in particular, methoxy is preferred.

As a substituent group of “alkyl which may be substituted” in R³ and R⁴,1 to 6 halogen atoms can be mentioned, respectively, and when 2 or moresubstituent groups are present, the substituent groups may be same ordifferent. In particular, fluorine atom is preferred. As a specificexample of “alkyl which may be substituted”, difluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, andthe like can be mentioned, and in particular, trifluoromethyl ispreferred.

As a substituent group of “alkoxy which may be substituted” in R³ andR⁴, alkoxy and 1 to 6 halogen atoms can be mentioned, respectively, andwhen 2 or more substituent groups are present, the substituent groupsmay be same or different. In particular, fluorine atom is preferred. Asa specific example of “alkoxy which may be substituted”,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,2,2,3,3,3-pentafluoropropoxy, and the like can be mentioned, and inparticular, difluoromethoxy and trifluoromethoxy are preferred.

As a substituent group of “alkyl which may be substituted” in R² andR^(2b), for example, 1 to 6 halogen atoms can be mentioned, and when 2or more substituent groups are present, the substituent groups may besame or different. As a particularly preferred substituent group,fluorine atom can be mentioned. As a specific example of the group,trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, andthe like can be mentioned.

As a substituent group of “alkoxy which may be substituted” in R² andR^(2b), for example, 1 to 6 halogen atoms can be mentioned, and when 2or more substituent groups are present, the substituent groups may besame or different. In particular, fluorine atom is preferred. As aspecific example of the group, trifluoromethoxy, 2,2,2-trifluoroethoxy,2,2,3,3,3-pentafluoropropoxy, and the like can be mentioned.

As a substituent group of “cycloalkyl which may be substituted” in R²and R^(2b), for example, alkyl which may be substituted with 1 to 7halogens can be mentioned, and when 2 or more substituent groups arepresent, the substituent groups may be same or different. As a specificexample of the group, 1-trifluoromethylcyclopropyl,1-trifluoromethylcyclobutyl, 1-trifluoromethylcyclohexyl,1-trifluoromethylcyclohexyl, and the like can be mentioned.

As a substituent group of “aromatic hydrocarbon group which may besubstituted” in R² and R^(2b), for example, 1 to 3 alkoxys can bementioned, and when 2 or more substituent groups are present, thesubstituent groups may be same or different. As a specific example ofthe group, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl,3,4-dimethoxyphenyl, and the like can be mentioned.

As a substituent group of “non-aromatic heterocyclic group which may besubstituted” in R² and R^(2b), for example, 1 to 3 halogen atoms can bementioned, and when 2 or more substituent groups are present, thesubstituent groups may be same or different. As a specific example ofthe group, 4-fluoropiperidino, 4,4-difluoropiperidino, and the like canbe mentioned.

As a substituent group of “aryloxy which may be substituted” in R² andR^(2b), for example, a group selected from halogen atom and cyano can bementioned. 1 to 3 of the substituent groups may be present, and when 2or more groups are present, the substituent groups may be same ordifferent. As a specific example of the group, 4-fluorophenyloxy,2,4-difluorophenyloxy, 3,4-difluorophenyloxy, 4-cyanophenyloxy, and thelike can be mentioned.

As a substituent group of “heteroaryloxy which may be substituted” in R²and R^(2b), for example, 1 to 3 alkyls can be mentioned, and when 2 ormore substituent groups are present, the substituent groups may be sameor different. As a specific example of the group,6-methylpyridin-2-yloxy, 6-methylpyrimidin-2-yloxy, and the like can bementioned.

Since the compound of the present invention has a basic group and anacidic group in the molecule, as a pharmaceutically acceptable saltthereof, an acid addition salt (for example, inorganic acid salt such ashydrochloride, sulfate, phosphate, hydrobromide; and organic acid saltsuch as acetate, fumarate, maleate, oxalate, citrate, methanesulfonate,benzenesulfonate, toluenesulfonate), and a salt with a base (forexample, alkali metal salt such as sodium salt, potassium salt; alkaliearth metal salt such as calcium salt; organic base salt such astriethylamine salt; and amino acid salt such as lysine salt; and thelike) can be mentioned.

In the compound of the present invention, an optical isomer based onasymmetric carbon may exist, and the compound of the present includesany isomer thereof and a mixture thereof. Further, if the compound ofthe present invention has a cycloalkanediyl, a cis form and a trans formmay be present, and in the compound of the present invention, a tautomerbased on an unsaturated bond such as carbonyl may be present. Thecompound of the present invention includes any isomer thereof and anymixture thereof.

Further, in the compound of the present invention a tautomer may existas shown by formulae as below due to hydrogen ion transfer in anaromatic heterocyclic ring. Even when the compound of the presentinvention is represented by one of chemical structure, any tautomerthereof and any mixture thereof are included.

Although the compound of the present invention or a pharmaceuticallyacceptable salt thereof can be also prepared by the process as below.

A process for preparing Compound (1) of the invention is explained belowby using Compound (1-A) and Compound (1-B) included in the Compound (1),and Compound (1) can be prepared in a manner similar to these processes.

[Method A]

Compound (1-A) can be prepared by the process as below:

(wherein HAL₁ represents halogen atom (such as chlorine atom and bromineatom), and the other symbols have the same meaning as above.)Step I:

The reaction of Compound (2) with hydroxylamine can be carried out, forexample, in an appropriate solvent, according to the process asdescribed in U.S. Pat. No. 5,576,447 and the like.

As the solvent, alcohols such as methanol and ethanol, ethers such astetrahydrofuran and 1,4-dioxane, water, or a mixture thereof can beused.

The reaction time is usually 3 to 16 hours, preferably 4 to 6 hours. Thereaction temperature is usually 5 to 100° C., preferably 25 to 80° C.

According to an ordinary method, the obtained product is treated withacetic acid-acetic anhydride, and subjected to a hydrogenation reactionin an appropriate solvent in the presence of palladium catalyst underhydrogen atmosphere to obtain Compound (3) as an acetate salt.

As the solvent, for example, alcohols such as methanol and ethanol,ethers such as tetrahydrofuran and 1,4-dioxane, acetic acid, or asolvent mixture thereof can be used.

As the palladium catalyst, for example, a catalyst such as palladiumcarbon, palladium black and palladium chloride can be used.

The reaction time differs depending on the catalyst, the solvent, andthe like to be used, and is usually 30 minutes to 18 hours, preferably30 minutes to 8 hours. The reaction temperature is usually 10 to 100°C., preferably 25 to 75° C.

Meanwhile, trialkylsilane such as triethylsilane can be used as ahydrogen source instead of hydrogen in the above hydrogenation reaction.

Further, Compound (3) can be prepared by reacting Compound (2) with analkoxy alkali metal in an appropriate solvent, followed by reacting withammonia source.

As the solvent, alcohols such as methanol and ethanol can be used.

As the alkoxy alkali metal, sodium methylate, sodium ethylate, potassiummethylate, and the like can be used.

As the ammonia source, an ammonium halide such as ammonium chloride andammonium bromide, an organic ammonium salt such as ammonium acetate andammonium propionate, ammonia and the like can be used.

Step II:

Compound (1-A) can be prepared, for example, by subjecting Compound (3)and Compound (4) to a cyclization reaction in an appropriate solvent inthe presence of base according to a method as described in I. M. Mallicket al., Journal of the American Chemical Society, 106(23), 7252-7254,1984, and the like.

As the solvent, alcohols such as methanol and ethanol, amides such as N,N-dimethyformamide and N-methylpyrrolidone, halogenated hydrocarbonssuch as methylene chloride and chloroform, tetrahydrofuran,acetonitrile, water, or a solvent mixture thereof can be used.

As the base, potassium hydrogen carbonate, potassium carbonate, sodiumethylate, and the like can be used.

The reaction time differs depending on the base, the solvent, and thelike to be used, and is usually 40 minutes to 18 hours, preferably 5hour to 12 hours. The reaction temperature is usually 18 to 100° C.,preferably 50 to 80° C.

Compound (1-A) can also be prepared by reacting, in an appropriatesolvent in the presence of acid, a product obtained by reacting Compound(3) and Compound (4) in the above method.

As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid,trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid, andthe like can be used.

As the solvent, for example, aromatic hydrocarbons such as benzene andtoluene, halogenated hydrocarbons such as chloroform and1,2-dichloroethane, ethers such as tetrahydrofuran and1,2-dimethoxyethane, organic acids such as formic acid and acetic acid,or a solvent mixture thereof can be used.

The reaction time differs depending on the acid, the solvent, and thelike to be used, and is usually 1 hour to 48 hours, preferably 4 hoursto 8 hours. The reaction temperature is usually 50 to 100° C.,preferably 70 to 90° C.

[Method B]

Compound (1-A) can also be prepared by the process as below:

(wherein Lv¹ represents B(OH)₂, or

HAL₂ represents halogen atom (such as chlorine atom and bromine atom),PG₁ represents amino protective group (preferably, substituted alkyl(such as 2-(trimethylsilyl)ethoxymethyl and benzyl)), and the othersymbols have the same meanings as the above.)

Step I;

Compound (7) can be prepared by subjecting Compound (5) and Compound (6)to Suzuki coupling reaction (for example, a reaction as described inAdvanced Organic Chemistry Part B (F. A. Carey & R. J. Sundberg,Springer) and the like) in an appropriate solvent in the presence of acatalyst and a base.

As the catalyst, palladium chloride, palladium acetate,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (PdCl₂(dppf)),tetrakistriphenylphosphine palladium and the like can be used, and ifnecessary, a ligand such as 1,1′-bis(diphenylphosphino)ferrocene,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-PHOS),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-PHOS) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) can also beadded.

As the base, an alkali metal such as sodium carbonate, potassiumcarbonate, potassium acetate, potassium phosphate, sodium hydroxide, andcesium carbonate, and the like can be used.

As the solvent, amides such as N, N-dimethyformamide, ethers such astetrahydrofuran, 1,4-dioxane and dimethoxyethane, aromatic hydrocarbonssuch as benzene and toluene, water, and a solvent mixture thereof can beused.

The reaction time differs depending on the amount or the kind of thereagent, the catalyst, the base, or the reaction solvent to be used, andthe reaction temperature, and is usually 2 to 48 hours, preferably 5 to12 hours.

The reaction temperature is from room temperature to 150° C., preferably60 to 120° C.

Step II:

Compound (1-A) can be prepared by deprotecting Compound (7).

The deprotection reaction of Compound (7) can be carried out, forexample, when PG₁ is 2-(trimethylsilyl)ethoxymethyl, by treatingCompound (7) with an acid (such as hydrochloric acid, trifluoroaceticacid and methanesulfonic acid) in an appropriate solvent (alcohols suchas methanol and ethanol, water, a solvent mixture thereof, and thelike), or by reacting Compound (7) with tetra-n-butylammonium fluoridein an appropriate solvent (ethers such as tetrahydrofuran, halogenatedhydrocarbons such as methylene chloride, and the like) to yield Compound(1-A). Further, for example, when PG₁ is benzyl, Compound (7) issubjected to a hydrogenation reaction in an appropriate solvent(alcohols such as methanol and ethanol, and the like) in the presence ofpalladium catalyst (such as palladium carbon and palladium hydroxide)under hydrogen atmosphere to prepare Compound (1-A).

Further, Compound (1-A) can also be prepared by carrying out a similarmethod to the above using the compounds represented by formulae asbelow:

(wherein each symbol has the meaning as the above),(hereinafter, referred to as Compound (5a) and Compound (6a)) instead ofCompound (5) and Compound (6), respectively.[Method C]

Compound (1-A) wherein X is —O— (hereinafter referred to as Compound(1-A-a)) can be prepared by the process as below:

(wherein each symbol has the same meaning as the above.)Step I:

Compound (10) can be prepared by subjecting Compound (8) and Compound(9) to Mitsunobu reaction (for example, a reaction as described inAdvanced Organic Chemistry Part B (F. A. Carey & R. J. Sundberg,Springer), Okuda, M.; Tomioka, K.; Tetrahedron Lett [TELEAY] 1994, 35(26), 4585-4586, and the like) in an appropriate solvent in the presenceof azodicarboxylates and phosphines.

As the azodicarboxylates, diethyl azodicarboxylate, di-t-butylazodicarboxylate, 1,1′-(azodicarbonyl)dipiperidine, and the like can beused.

As the phosphines, tri-aryl phosphines such as triphenylphosphine,tri-alkylphosphines such as tri-n-butylphosphine, and the like can beused.

As the solvent, for example, ethers such as tetrahydrofuran, 1,4-dioxaneand diethylether, aromatic hydrocarbons such as benzene, toluene andxylene, halogenated hydrocarbons such as methylene chloride,1,2-dichloroethane and chloroform, or a solvent mixture thereof can beused.

The reaction time differs depending on the reagent, the solvent, and thelike to be used, and is usually 30 minutes to 24 hours, preferably 3 to12 hours. The reaction temperature is usually 5° C. to 150° C.,preferably room temperature to 80° C.

Step II:

The deprotection reaction of Compound (10) can be carried out in amanner similar to Step II of Method B.

[Method D]

Compound (1-A) wherein X is a single bond and Y^(a) is cycloalkyl whichmay be substituted (hereinafter, referred to as Compound (1-A-b)) can beprepared by the process as below:

(wherein a group:

represents cycloalkenyl which may be substituted, Y² representscycloalkyl which may be substituted, Lv² represents halogen atom (suchas chlorine atom and bromine atom) or trifluoromethanesulfonyloxy group,and Lv³ represents B(OH)₂ or

and the other symbols have the same meanings as the above.)

Step I:

Compound (13) can be prepared by a coupling reaction of Compound (11)with Compound (12), which can be carried out in a manner similar to StepI of Method B.

Step II:

Compound (14) can be prepared by subjecting Compound (13) to ahydrogenation reaction in an appropriate solvent in the presence of apalladium catalyst under hydrogen atmosphere.

As the solvent, alcohols such as methanol and ethanol, ethers such astetrahydrofuran and 1,4-dioxane, or a solvent mixture thereof can beused.

As the palladium catalyst, a catalyst such as palladium carbon andpalladium black can be used.

The reaction time differs depending on the catalyst, the solvent, andthe like to be used, and is usually 1 hour to 24 hours, preferably 1hour to 12 hours. The reaction temperature is usually 50 to 100° C.,preferably 60 to 100° C.

Step III:

The deprotection reaction of Compound (14) can be carried out in amanner similar to Step II of Method B.

[Method E]

Compound (1-A) wherein R¹ is halogen (hereinafter, referred to asCompound (1-A-d)) and Compound (1-A) wherein R¹ is alkyl (hereinafter,referred to as Compound (1-A-e)) can be prepared by the process asbelow:

(wherein HAL₃ represents halogen atom (such as chlorine atom and bromineatom), and R^(1a) represents alkyl, and Lv⁴ represents B(OH)₂ or

and the other symbols have the same meaning as above.)Step I:

Compound (1-A-d) can be prepared by reacting Compound (1-A-c) with ahalogenating agent in an appropriate solvent, if necessary, in thepresence of base.

As the halogenating agent, N-chlorosuccinimide, N-bromosuccinimide, andthe like can be used.

As the solvent, a halogenated hydrocarbon such as chloroform andmethylene chloride, N, N-dimethyformamide, acetonitrile, ethanol, andthe like can be used.

As the base, imidazole, triethylamine, and the like can be used.

The reaction time differs depending on the reagent, the solvent, and thelike to be used, and is usually 1 hour to 22 hours, preferably 2 hoursto 15 hours. The reaction temperature is usually 0° C. to 60° C.,preferably room temperature to 50° C.

Step II:

The reaction of Compound (1-A-d) with Compound (15) can be carried outin a manner similar to Step I of Method B.

[Method F]

Compound (2) wherein X is —O— (hereinafter, referred to as Compound(2a)) can also be prepared by the process as below:

(wherein HAL₄ and HAL₅ represent halogen atom (such as chlorine atom andbromine atom), and Lv⁵ represents B(OH)₂ or

and the other symbols have the same meanings as the above.)Step I:

The coupling reaction of Compound (16) with Compound (9) can be carriedout in a manner similar to Step I of Method C.

Step II:

Compound (18) can be prepared by reacting Compound (17) with a boronicacid ester in an appropriate solvent in the presence of a palladiumcatalyst, a ligand and a base.

As the solvent, ethers such as 1,4-dioxane, dimethyl sulfoxide, aromatichydrocarbons such as toluene, and the like can be used.

As the palladium catalyst, palladium acetate, dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (PdCl₂(dppf)) and the like can beused.

As the ligand, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-PHOS),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-PHOS),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and the likecan be used.

As the base, potassium acetate, potassium phosphate, and the like can beused.

As the boronic acid ester, bis(pinacolato)diboron, trialkoxyboron, andthe like can be used.

The reaction time differs depending on the catalyst, the solvent, andthe like to be used, and is usually 1 hour to 24 hours, preferably 2hours to 12 hours. The reaction temperature is usually 50 to 130° C.,preferably 60 to 100° C.

Step III:

The coupling reaction of Compound (18) with Compound (19) can be carriedout in a manner similar to Step I of Method B.

[Method G]

Compound (8), and Compound (11a) which is Compound (11) wherein Lv² istrifluoromethanesulfonyloxy can be prepared by the process as below:

(wherein PG₂ represents a hydroxyl group-protective group (preferably,substituted alkyl (such as benzyl)), Lv⁶ represents B(OH)₂, or

and each symbol has the same meaning as above.)Step I:

The coupling reaction of Compound (6) with Compound (20) can be carriedout in a manner similar to Step I of Method B.

Step II:

Compound (8) can be prepared by deprotecting PG₂ of Compound (21).

The deprotecting reaction of PG₂ can be carried out, for example, whenPG₂ is a benzyl group, by subjecting Compound (21) to a hydrogenationreaction in an appropriate solvent (alcohols such as methanol andethanol) in the presence of a palladium catalyst (such as palladiumcarbon and palladium hydroxide) under hydrogen atmosphere to prepareCompound (8).

Step III:

Compound (11a) can be prepared by reacting Compound (8) withtrifluoromethanesulfonic anhydride in an appropriate solvent(halogenated hydrocarbons such as methylene chloride and chloroform,ethers such as tetrahydrofuran and diethylether, and the like) in thepresence of a base (such as triethylamine, N,N-diisopropylethylamine and2,6-lutidine) at 0° C. to 25° C. for 1 hour to 8 hours.

[Method H]

Compound (6) can also be prepared by the process as below:

(wherein each symbol has the same meaning as above.)

Step I and Step II in the present reaction can be carried out in amanner similar to Step I and Step II of Method A.

Step III:

Compound (6) can be prepared by protecting the amino group of Compound(24). For example, when PG₁ is 2-(trimethylsilyl)ethoxymethyl group,Compound (6) can be prepared by reacting Compound (24) with2-(trimethylsilyl)ethoxymethyl chloride in an appropriate solvent in thepresence of a base.

As the solvent, for example, an aprotic polar solvent such as N,N-dimethyformamide, N,N-dimethylacetamide and N-methylpyrrolidone can beused.

As the base, for example, an alkali metal hydride (such as sodiumhydride and lithium hydride), an alkali metal carbonate (such aspotassium carbonate) can be used.

[Method I]

Compound (6) wherein R¹ is hydrogen (hereinafter, referred to asCompound (6a)) can be prepared by the process as below:

(wherein each symbol has the same meaning as above.)Step I:

Compound (27) can be prepared by reacting Compound (25) with Compound(26) and ammonia in an appropriate solvent.

As the solvent, an alcoholic solvent such as methanol and ethanol,water, and the like can be used.

The reaction time is usually 1 hour to 24 hours, preferably 5 hours to12 hours. The reaction temperature is usually 5° C. to 60° C.,preferably room temperature to 40° C.

Step II:

The present reaction can be carried out in a manner similar to Step IIIof Method H.

[Method J]

Compound (27) can also be prepared by the process as below:

(wherein HAL₆ and HAL₇ are the same or different and represent a halogenatom (such as chlorine atom, bromine atom and iodine atom).)

Compound (27) can be prepared by reacting Compound (25) with Compound(28) and ammonia in an appropriate solvent in the presence of a baseaccording to a method as described in J. J. Baldwin et al., Journal ofMedicinal Chemistry, 29(6), 1065-1080, 1986 and the like.

As the solvent, alcohols such as methanol and ethanol, water, and thelike can be used.

As the base, alkali metal acetate (for example, sodium acetate) and thelike can be used.

The present reaction can be carried out by stirring Compound (28) in anaqueous solvent in the presence of a base at 90 to 100° C. for 30minutes to 1 hour, and then adding Compound (25) and ammonia water tothe reaction system under cooling, and further stirring underice-cooling to 50° C. for 1 day to 2 days. The reaction is preferablycarried out at room temperature to 40° C.

[Method K]

Compound (4) can also be prepared by the process as below:

(wherein each symbol has the same meaning as above.)

Compound (4) can be prepared by reacting Compound (29) with ahalogenating agent in an appropriate solvent (for example, halogenatedhydrocarbons such as methylene chloride).

As the halogenating agent, for example, N-bromosuccinimide,N-chlorosuccinimide, copper bromide, hydrobromic acid,benzyltrimethylammonium tribromide, and the like can be mentioned.

[Method L]

Compound (4) wherein R¹ is hydrogen (hereinafter, referred to asCompound (4a)) can also be prepared by the process as below:

(wherein each symbol has the same meaning as above.)

Compound (4a) can be prepared by reacting Compound (30) with oxalylchloride in an appropriate solvent, and reacting withtrimethylsilyldiazomethane, then by subjecting to a halogenation in anappropriate solvent.

As the solvent for the reaction of Compound (30) with oxalyl chloride,halogenated hydrocarbon such as chloroform and methylene chloride,ethers such as tetrahydrofuran, and the like can be used.

The present reaction can be carried out by adding a catalystic amount ofN, N-dimethyformamide at −20 to 40° C., preferably under ice-cooling toroom temperature.

As the solvent for the reaction with trimethylsilyldiazomethane,acetonitrile, ethers such as tetrahydrofuran, and halogenatedhydrocarbon such as chloroform and methylene chloride and the like canbe used.

The present reaction can be carried out at −20 to 40° C., preferablyunder ice-cooling to room temperature.

The halogenation can be carried out in a manner similar to thehalogenation of Method K.

[Method M]

A compound of the general formula (B) wherein X^(B) is a single bond,and Y^(B) is phenyl which may be substituted (hereinafter, referred toas Compound (B1)) can be prepared by the process as below:

(wherein X^(B1) represents a single bond, Y^(B1) represents phenyl whichmay be substituted, Lv⁷ represents a halogen atom (such as chlorine atomand bromine atom), B(OH)₂ or

and the other symbols have the same meanings as above.Step I:(1) When Lv⁷ represents B(OH)₂ or

Compound (33) can be prepared by reacting Compound (31) with Compound(32) in an appropriate solvent in the presence of a catalyst such as acopper catalyst, and a base.

As the solvent, halogenated hydrocarbons such as methylene chloride and1,2-dichloroethane, aromatic hydrocarbons such as toluene, polar solventsuch as acetonitrile, dimethylformamide and dimethylsulfoxide, and thelike can be used.

As the catalyst, a copper catalyst such as copper acetate, and the likecan be used.

As the base, organic base such as triethylamine and pyridine, and thelike can be used.

Further, if necessary, a dehydrating agent such as molecular sieve canbe used.

The reaction time differs depending on the reagent, the solvent, and thelike to be used, and is usually 12 hours to 144 hours, preferably 24hours to 48 hours. The reaction temperature is usually 20° C. to 90° C.,preferably 20° C. to 40° C.

(2) When Lv⁷ is halogen, Compound (33) can be prepared by reactingCompound (31) with Compound (32) in an appropriate solvent in thepresence of a base, and if necessary in the presence of a palladiumcatalyst and a ligand.

As the solvent, ethers such as tetrahydrofuran, 1 4-dioxane anddimethoxyethane, aromatic hydrocarbons such as benzene and toluene,halogenated hydrocarbons such as methylene chloride and1,2-dichloroethane, water, N, N-dimethyformamide, dimethylsulfoxide, ora solvent mixture thereof can be used.

As the base, an inorganic base such as sodium carbonate, potassiumcarbonate, potassium acetate, potassium phosphate, sodium hydroxide andcesium carbonate, an organic base such as triethylamine,N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-en (DBU) andN-methylmorpholine, sodium tert-butoxide, and the like can be used.

As the catalyst, palladium chloride, palladium acetate,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (PdCl₂(dppf)),tetrakistriphenylphosphinepalladium and the like can be used, and ifnecessary, a ligand such as 1,1′-bis(diphenylphosphino)ferrocene,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-PHOS),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-PHOS),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl (RuPhos) andthe like can be added.

The reaction time differs depending on the reagent, the solvent, and thelike to be used, and is usually 1 hour to 24 hours, preferably 3 hoursto 15 hours. The reaction temperature is usually 70° C. to 120° C.,preferably 80° C. to 100° C.

In the present reaction, the reaction can be accelerated by microwaveirradiation.

Step II:

Compound (B1) can be prepared by deprotecting Compound (33), which canbe carried out in a manner similar to Step II of Method B.

[Method N]

The compound of the general formula (B) or the general formula (C)(hereinafter, referred to as Compound (X)) can also be prepared by theprocess as below:

(wherein a group:

represents piperidine, or piperazine which may be substituted with Pand/or Q; B^(X), X^(X), Y^(X), R^(1X) and R^(2X) represent a groupcomprising B¹ and B³, X^(B) and X^(C), Y^(B) and Y^(C), R^(1B) andhydrogen atom, and R^(2B) and R^(2C), respectively, and the othersymbols have the same meanings as above.)

Step I and Step II in the present reaction can be carried out in amanner similar to Step I and Step II of Method M.

[Method O]

The compound of the general formula (C) wherein X^(C) is —O— or —OCH₂—and Y^(C) is phenyl which may be substituted (hereinafter, referred toas Compound (C1)) can be prepared by the process as below:

(wherein Y^(C1) represents phenyl which may be substituted, n representsan integer from 0 to 1, and the other symbols have the same meanings asabove.)

Step I and Step II of the present reaction can be carried out in amanner similar to Step I of Method N and Step I of Method C, and furtherPG₁ is deprotected to prepare Compound (C1).

[Method P]

Compound (34) wherein a group:

is piperidine, and X is —O— (hereinafter, referred to as Compound (34a))can be prepared by the process as below:

(wherein each symbol has the same meaning as above.)Compound (34) can be prepared by subjecting Compound (36) to a reductionreaction.

The present reaction can be carried out by reacting Compound (36) with areducing agent (such as sodium borohydride) in an appropriate solvent(for example, alcohols such as methanol and ethanol, and the like), andthen subjecting to a hydrogenation reaction in the presence of acatalyst (such as palladium carbon) to prepare Compound (34a).

[Method Q]

The compound represented by the general formula (D) can be prepared bythe process as below:

(wherein Lv⁸ represents B(OH)₂, or

and the other symbols have the same meanings as above.)

Step I to Step III of the present reaction can be carried out in amanner similar to Step I to Step III of Method D.

[Method R]

Compound (1-B) can be prepared by the process as below:

(wherein Lv⁹ represents B(OH)₂ or

HAL₈ represents a halogen atom (such as chlorine atom and bromine atom),PG₃ represents an amino-protective group (preferably, substituted alkyl(2-(trimethylsilyl)ethoxymethyl, benzyl, and the like), and the othersymbols have the same meanings as above.)

Step I:

Compound (42) can be prepared by subjecting Compound (40) and Compound(41) to Suzuki coupling reaction (for example, a reaction as describedin Advanced Organic Chemistry Part B (F. A. Carey & R. J. Sundberg,Springer), and the like) in an appropriate solvent in the presence of acatalyst and a base.

As the catalyst, palladium chloride, palladium acetate,[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloridedichloromethane complex (PdCl₂(dppf)CH₂Cl₂),tetrakistriphenylphosphinepalladium, and the like can be used, and ifnecessary a ligand such as 1,1′-bis(diphenylphosphino)ferrocene,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-PHOS),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-PHOS),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and the likecan be added.

As the base, an alkali metal such as sodium carbonate, potassiumcarbonate, potassium acetate, potassium phosphate, sodium hydroxide, andcesium carbonate, and the like can be used.

As the solvent, amides such as N, N-dimethyformamide, ethers such astetrahydrofuran, 1,4-dioxane and dimethoxyethane, aromatic hydrocarbonssuch as benzene and toluene, water, or a solvent mixture thereof can beused.

The reaction time differs depending on the amount or the kind of thereagent, the catalyst, the base, or the reaction solvent to be used andthe reaction temperature, and is usually 2 to 48 hours, preferably 5 to12 hours.

The reaction temperature is room temperature to 150° C., preferably 60to 120° C.

Step II:

Compound (1-B) can be prepared by deprotecting Compound (42).

The deprotection reaction of Compound (42) can be carried out, forexample, when PG₃ is 2-(trimethylsilyl)ethoxymethyl, by treatingCompound (42) with an acid (such as hydrochloric acid, trifluoroaceticacid and methanesulfonic acid) in an appropriate solvent (such asalcohols such as methanol and ethanol, water, or solvent mixturethereof) to prepare Compound (1-B). Further, Compound (1-B) can also beprepared by reacting Compound (42) with tetra-n-butylammonium fluoridein an appropriate solvent (ethers such as tetrahydrofuran, orhalogenated hydrocarbons such as methylene chloride and the like).

Compound (1-B) can also be prepared by carrying out a similar method tothe above using the compounds represented by following formulae:

(wherein each symbol has the same meaning as above,)

(hereinafter, referred to as Compound (40a) and Compound (41a)), insteadof Compound (40) and Compound (41).

[Method S]

Compound (1-B) wherein R^(2b) is alkyl which may be substituted, anaromatic hydrocarbon group which may be substituted, or cycloalkyl whichmay be substituted (hereinafter, referred to as Compound (1-B-a)) can beprepared by the process as below:

(wherein R^(2b1) represents alkyl which may be substituted, an aromatichydrocarbon group which may be substituted, or cycloalkyl which may besubstituted, R^(z) represents alkyl, and the other symbols have the samemeanings as above.)Step I:

Compound (44) can be prepared by (i) reacting Compound (43) withhydroxylamine followed by treatment with acetic acid-acetic anhydrideand then a hydrogenation, or (ii) reacting Compound (43) with an alcoholin the presence of an acid, followed by reaction with ammonia or (iii)by reacting Compound (43) with lithium hexamethyldisilazane followed bytreatment with an acid.

Reaction (i)

The reaction of Compound (43) with hydroxylamine can be carried out, forexample, in an appropriate solvent, according to a method as describedin U.S. Pat. No. 5,576,447 and the like.

As the solvent, alcohols such as methanol and ethanol, ethers such astetrahydrofuran and 1,4-dioxane, water, and a solvent mixture thereofcan be used.

The reaction time is usually 3 to 24 hours, preferably 4 to 18 hours.The reaction temperature is usually 5 to 100° C., preferably 25 to 80°C.

Thus obtained product is treated with acetic acid-acetic anhydride, andsubjected to a hydrogenation reaction in an appropriate solvent in thepresence of a palladium catalyst under hydrogen atmosphere according toan ordinary method to prepare Compound (44).

As the solvent, alcohols such as methanol and ethanol, ethers such astetrahydrofuran and 1,4-dioxane, and a solvent mixture thereof can beused.

As the palladium catalyst, a catalyst such as palladium carbon andpalladium black can be used.

The reaction time differs depending on the catalyst, the solvent, andthe like to be used, and is usually 30 minutes to 18 hours, preferably 2hours to 8 hours. The reaction temperature is usually 10 to 100° C.,preferably 25 to 50° C.

In the hydrogenation reaction, trialkylsilane such as triethylsilane canbe used as the hydrogen source instead of hydrogen.

Reaction (ii)

The reaction of Compound (43) with an alcohol can be carried outaccording to a method as described in Chemische Berichte, 1878, 11, 9.

As the acid, hydrochloric acid, sulfuric acid, and the like can be used.

As the alcohol, methanol, ethanol, propanol, butanol, and the like canbe used.

The reaction time in the reaction of Compound (43) and an alcohol isusually 2 hours to 24 hours, preferably 5 hours to 20 hours. Thereaction temperature is usually 5 to 50° C., preferably 25 to 50° C.

In the reaction with ammonia, a solvent may be used, and as the solvent,alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, asolvent mixture thereof, and the like can be used.

The reaction time in the reaction with ammonia is usually 3 hours to 24hours, preferably 8 hours to 20 hours. The reaction temperature isusually 5 to 50° C., preferably 25 to 50° C.

Reaction (iii)

The reaction of Compound (43) with lithium hexamethyldisilazane can becarried out according to a method as described in J. Organomet. Chem.,1987, 331, 21, 161-167.

As the solvent, ethers such as tetrahydrofuran, and the like can beused.

The reaction time in the reaction with lithium hexamethyldisilazane isusually 1 hour to 24 hours, preferably 2 hours to 18 hours. The reactiontemperature is usually 0 to 50° C., preferably 5 to 30° C.

As the acid in the treatment with an acid, hydrochloric acid,hydrobromic acid, and the like can be used.

In the treatment with an acid, a solvent may be used, and as thesolvent, ethers such as tetrahydrofuran and dioxane and the like can beused.

The reaction time in the treatment with an acid differs depending on theacid, the solvent and the like to be used, and is usually 30 minutes to24 hours, preferably 1 hour to 18 hours. The reaction temperature isusually 0 to 50° C., preferably 5 to 30° C.

Step II:

Compound (1-B-a) can be prepared by reacting Compound (44) with Compound(45) and hydrazine in an appropriate solvent in the presence or absenceof a base.

As the solvent, ethers such as tetrahydrofuran and 1,4-dioxane,halogenated hydrocarbons such as 1,2-dichloroethane and carbontetrachloride, alcohols such as methanol and ethanol, a solvent mixturethereof, and the like can be used.

As the base, an alkali metal carbonate such as potassium carbonate andsodium hydrogencarbonate, alkali metal alkoxide such as sodiummethoxide, alkali metal hydroxide such as sodium hydroxide and potassiumhydroxide, and the like can be used.

Hydrazine used in the present reaction may be in a form of salt (forexample, hydrochloride salt) and/or may be a hydrate.

The reaction time in the reaction with hydrazine is usually 30 minutesto 12 hours, preferably 30 minutes to 8 hours. The reaction temperatureis usually 25 to 100° C., preferably 50 to 80° C.

Further, a hydrazide compound (45a) represented by the formula as below:

(wherein each symbol has the same meaning as above)may be used instead of Compound (45) and hydrazine to obtain Compound(1-B-a) according to a method as described in Tetrahedron Letters, 1987,28, 5133-5136.[Method T]

Compound (1-B) wherein X is —O— (hereinafter, referred to as Compound(1-B-b) can be prepared by the process as below:

(wherein each symbol has the same meaning as above.)Step I:

Compound (48) can be prepared by subjecting Compound (46) and Compound(47) to Mitsunobu reaction (for example, a reaction as described inAdvanced Organic Chemistry Part B (F. A. Carey & R. J. Sundberg,Springer), Okuda, M.; Tomioka, K.; Tetrahedron Lett [TELEAY] 1994, 35(26), 4585-4586, and the like) in an appropriate solvent in the presenceof azodicarboxylates and phosphines.

As the azodicarboxylates, diethyl azodicarboxylate, di-t-butylazodicarboxylate, 1,1′-(azodicarbonyl)dipiperidine, and the like can beused.

As the phosphines, triarylphosphines such as triphenylphosphine,trialkylphosphines such as tri-n-butylphosphine, and the like can beused.

As the solvent, ethers such as tetrahydrofuran, 1,4-dioxane anddiethylether, aromatic hydrocarbons such as benzene, toluene and xylene,halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethaneand chloroform, or a solvent mixture thereof can be used.

The reaction time differs depending on the reagent, the solvent, and thelike to be used, and is usually 30 minutes to 24 hours, preferably 1hour to 12 hours. The reaction temperature is usually 0° C. to 100° C.,preferably 25° C. to 80° C.

Step II:

The deprotection reaction of Compound (48) can be carried out in amanner similar to Step II of Method R.

[Method U]

Compound (1-B) wherein X is a single bond and Y^(b) is cycloalkyl whichmay be substituted (hereinafter, referred to as Compound (1-B-c) can beprepared by the process as below:

(wherein a group

represents cycloalkenyl which may be substituted, Y² representscycloalkyl which may be substituted, Lv¹⁰ represents a halogen atom(such as chlorine atom and bromine atom), or trifluoromethanesulfonyloxygroup, Lv¹¹ represents B(OH)₂ or

and the other symbols have the same meanings as above.)Step I:

Compound (51) can be prepared by a coupling reaction of Compound (49)with Compound (50), which can be carried out in a manner similar to StepI of Method R.

Step II:

Compound (52) can be prepared by subjecting Compound (51) to ahydrogenation reaction in an appropriate solvent in the presence of apalladium catalyst under hydrogen atmosphere.

As the solvent, alcohols such as methanol and ethanol, ethers such astetrahydrofuran and 1,4-dioxane, or a solvent mixture thereof can beused.

As the palladium catalyst, a catalyst such as palladium carbon andpalladium black can be used.

The reaction time differs depending on the catalyst, the solvent, andthe like to be used, and is usually 1 hour to 24 hours, preferably 1hour to 12 hours. The reaction temperature is usually 20 to 50° C.,preferably 20 to 40° C.

Step III:

The deprotection reaction of Compound (52) can be carried out in amanner similar to Step II of Method R.

[Method V]

Compound (1-B) wherein R^(2b) is alkoxy (hereinafter, referred to asCompound (1-B-d)) can be prepared by the process as below:

(wherein R^(2b2) represents alkoxy, and the other symbols have the samemeanings as above.)

Compound (1-B-d) can be prepared by reacting Compound (53) with oxalylchloride or thionyl chloride in an appropriate solvent in the presenceor absence of N, N-dimethyformamide, then reacting with potassiumthiocyanate, and reacting with an alcohol and hydrazine.

As the solvent in the reaction with oxalyl chloride or thionyl chloride,halogenated hydrocarbons such as methylene chloride, ethers such astetrahydrofuran, and the like can be used.

The reaction time in the reaction with oxalyl chloride or thionylchloride is usually 30 minutes to 5 hours, preferably 1 hour to 3 hours.The reaction temperature is usually 0 to 60° C., preferably 20 to 40° C.

As the solvent in the reaction with potassium thiocyanate, aromatichydrocarbons such as toluene, halogenated hydrocarbons such as methylenechloride, and the like can be used.

The reaction time in the reaction with potassium thiocyanate is usually2 hours to 24 hours, preferably 1 hour to 3 hours. The reactiontemperature is usually 0 to 60° C., preferably 20 to 40° C.

As the alcohol in the present reaction, methanol, ethanol, propanol,isopropanol, butanol, t-butanol, and the like can be used.

The reaction time in the reaction with alcohol is usually 30 minutes to5 hours, preferably 1 hour to 3 hours. The reaction temperature isusually 0 to 100° C., preferably 20 to 40° C.

The reaction time in the reaction with hydrazine is usually 2 hours to24 hours, preferably 1 hour to 3 hours. The reaction temperature isusually 0 to 100° C., preferably 50 to 80° C.

Hydrazine used in the present reaction may be in a form of salt (forexample, hydrochloride salt), and/or may be in a hydrate.

[Method W]

Compound (43) wherein X is —O— (hereinafter, referred to as Compound(43a) can be prepared by the process as below:

(wherein HAL₉ and HAL₁₀ represent a halogen atom (such as chlorine atomand bromine atom), and the other symbols have the same meanings asabove.)Step I:

The coupling reaction of Compound (54) with Compound (47) can be carriedout in a manner similar to Step I of Method T.

Step II:

Compound (56) can be prepared by reacting Compound (55) with a boronicacid ester in an appropriate solvent in the presence of a palladiumcatalyst, a ligand and a base.

As the solvent, ethers such as 1,4-dioxane, dimethylsulfoxide, aromatichydrocarbons such as toluene, and the like can be used.

As the palladium catalyst, palladium acetate,[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloridedichloromethane complex (PdCl₂(dppf)CH₂Cl₂) and the like can be used.

As the ligand, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-PHOS),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-PHOS),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and the likecan be used.

As the base, potassium acetate, potassium phosphate, and the like can beused.

As the boronic acid ester, bis(pinacolato)diboron, trialkoxyboron, andthe like can be used.

The reaction time differs depending on the catalyst, the solvent, andthe like to be used, and is usually 1 hour to 24 hours, preferably 2hours to 12 hours. The reaction temperature is usually 50 to 130° C.,preferably 60 to 100° C.

Step III:

The coupling reaction of Compound (56) with Compound (57) can be carriedout in a manner similar to Step I of Method R.

[Method X]

Compound (41) wherein R^(2b) is alkyl which may be substituted, aromatichydrocarbon group which may be substituted, or cycloalkyl which may besubstituted (hereinafter, referred to as Compound (41b)) can be preparedby the process as below:

(wherein each symbol has the same meaning as above.)Steps I and II:

Compound (60) can be prepared in a manner similar to Step I and Step IIof Method S.

Step III:

Compound (41b) can be prepared by protecting the amino group of Compound(60). For example, when PG₃ is 2-(trimethylsilyl)ethoxymethyl group, itcan be prepared by reacting Compound (60) with2-(trimethylsilyl)ethoxymethyl chloride in an appropriate solvent in thepresence of a base.

As the solvent, an aprotic polar solvent such as N,N-dimethyformamide,N,N-dimethylacetamide and N-methylpyrrolidone can be used.

As the base, an alkali metal hydride such as sodium hydride andpotassium hydride, or an alkali metal carbonate such as potassiumcarbonate and sodium carbonate can be used.

[Method Y]

Compound (41) wherein R^(2b) is alkylthio (hereinafter, referred to asCompound (41c)) can be prepared by the process as below:

wherein HAL₁₁ represents a halogen atom such as chlorine atom, bromineatom and iodine atom), R^(2b3) represents alkyl, and the other symbolshave the same meanings as above.Step I:

Compound (63) can be prepared by reacting Compound (61) with Compound(62) in an appropriate solvent in the presence of methyl iodide, carbondisulfide and a base, and by reacting the obtained product withhydrazine in an appropriate solvent.

As the solvent in the reaction of Compound (61) with Compound (62),amides such as N,N-dimethyformamide, ethers such as tetrahydrofuran, andthe like can be used.

As the base in the reaction of Compound (61) with Compound (62), alkylmetal hydride such as sodium hydride and potassium hydride, and the likecan be used.

The reaction time in the reaction of Compound (61) with Compound (62) isusually 1 hour to 24 hours, preferably 2 hours to 12 hours. The reactiontemperature is usually −10 to 40° C., preferably −10 to 25° C.

As the solvent in the reaction with hydrazine, ethers such astetrahydrofuran, alcohols such as methanol and ethanol, a solventmixture thereof, and the like can be used.

Hydrazine used in the present reaction may be in a form of salt and/ormay be a hydrate.

The reaction time in the reaction with hydrazine is usually 30 minutesto 8 hours, preferably 1 hour to 5 hours. The reaction temperature isusually 0 to 40° C., preferably 0 to 25° C.

Step II:

The reaction from Compound (63) to Compound (41c) can be carried out ina manner similar to Step III of Method X.

[Method Z]

Compound (63) can also be prepared by the process as below:

(wherein each symbol has the same meaning as above.)Step I:

Compound (65) can be prepared by reacting Compound (64) with oxalylchloride or thionyl chloride in an appropriate solvent in the presenceor absence of N,N-dimethylformamide, followed by reaction withthiosemicarbazide in an appropriate solvent in the presence of a base.

As the solvent in the reaction with oxalyl chloride or thionyl chloride,halogenated hydrocarbons such as methylene chloride, ethers such astetrahydrofuran, and the like can be used.

The reaction time in the reaction with oxalyl chloride or thionylchloride is usually 30 minutes to 5 hours, preferably 1 hour to 3 hours.The reaction temperature is usually 0 to 60° C., preferably 20 to 40° C.

As the solvent in the reaction with thiosemicarbazide, ethers such astetrahydrofuran, halogenated hydrocarbons such as methylene chloride,and the like can be used.

As the base in the reaction with thiosemicarbazide, pyridine,triethylamine, and the like can be used.

The reaction time in the reaction with thiosemicarbazide is usually 2hours to 24 hours, preferably 1 hour to 3 hours. The reactiontemperature is usually 25 to 100° C., preferably 80 to 100° C.

Step II:

Compound (63) can be prepared by reacting Compound (65) with Compound(62) in an appropriate solvent in the presence of an alkali metal basesuch as an alkali metal hydroxide and potassium carbonate.

As the solvent, a mixed solvent of alcohol such as methanol and ethanol,and water, and the like can be used.

As the alkali metal hydroxide base, sodium hydroxide, potassiumhydroxide, and the like can be used.

The reaction time is usually 30 minutes to 5 hours, preferably 1 hour to3 hours. The reaction temperature is usually 0 to 40° C., preferably 0to 25° C.

[Method AA]

Compound (41) wherein R^(2b) is alkoxy which may be substituted, aryloxywhich may be substituted, heteroaryloxy which may be substituted,cycloalkyloxy, cycloalkylalkoxy, or non-aromatic heterocycle having abond at the nitrogen atom which may be substituted (hereinafter,referred to as Compound (41d)) can be prepared by the process as below:

(wherein R^(2b4) represents alkoxy which may be substituted, aryloxywhich may be substituted, heteroaryloxy which may be substituted,cycloalkyloxy, cycloalkylalkoxy, or non-aromatic heterocycle having abond at the nitrogen atom which may be substituted (preferably,piperidino, 1-piperazinyl, morpholino, and the like), and the othersymbols have the same meanings as above.)Step I:

Compound (66) can be prepared by reacting Compound (63a) with anoxidizing agent in an appropriating solvent.

As the solvent, halogenated hydrocarbons such as methylene chloride andchloroform, ethers such as tetrahydrofuran, and the like can be used.

As the oxidizing agent, m-chloroperoxybenzoic acid and the like can beused.

The reaction time is usually 30 minutes to 24 hours, preferably 1 hourto 12 hours. The reaction temperature is usually 0 to 40° C., preferably0 to 25° C.

Step II:

Compound (41d) can be prepared by reacting Compound (66) with Compound(67) in an appropriate solvent in the presence of a base.

As the solvent, amides such as N, N-dimethyformamide andN-methylpyrrolidone, ethers such as tetrahydrofuran and 1,4-dioxane, asolvent mixture thereof, and the like can be used.

As the base, an alkali metal hydride such as sodium hydride andpotassium hydride, an alkali metal carbonate such as potassium carbonateand sodium carbonate, an organic bases such as triethylamine andN,N-diisopropylethylamine, and the like can be used.

The reaction time is usually 10 minutes to 24 hours, preferably 10minutes to 12 hours. The reaction temperature is usually 0 to 150° C.,preferably 0 to 120° C.

[Method AB]

Compound (41) wherein R^(2b) is alkoxy which may be substituted(hereinafter, referred to as Compound (41e)) can be prepared by theprocess as below:

(wherein R^(2b5) represents alkyl which may be substituted, and theother symbols have the same meanings as above.)Step I:

Compound (69) can be prepared by reacting Compound (68) with a cyanogenhalide (such as bromo cyanide) in an appropriate solvent in the presenceof a base, according to a process as described in Justus Liebigs Annalender Chemie, 1955, 597, 157-165 and the like.

As the solvent, ethers such as 1,4-dioxane, halogenated hydrocarbonssuch as methylene chloride, acetonitrile, and the like can be used.

As the base, an alkali metal carbonate such as sodium hydrogencarbonate,an alkali metal hydroxide such as sodium hydroxide, and the like can beused.

The reaction time is usually 1 hour to 48 hours, preferably 2 hours to24 hours. The reaction temperature is usually 0 to 100° C., preferably25 to 80° C.

Step II:

Compound (71) can be prepared by reacting Compound (69) with Compound(70) in the present of an alkali metal hydroxide base.

As the alkali metal hydroxide base, sodium hydroxide, potassiumhydroxide, and the like can be used.

The reaction time is usually 1 hour to 24 hours, preferably 3 hours to12 hours. The reaction temperature is usually 50 to 100° C., preferably60 to 90° C.

Step III:

Compound (41e) can be prepared by protecting Compound (71) in a mannersimilar to Step III of Method X.

[Method AC]

Compound (41) wherein R^(2b) is non-aromatic heterocyclic group having abond at the nitrogen atom which may be substituted (preferably,piperidino, 1-piperazinyl, morpholino, and the like) (hereinafter,referred to as Compound (410) can be prepared by the process as below:

(wherein R^(2b6) represents non-aromatic heterocyclic group having abond at the nitrogen atom which may be substituted (preferably,piperidino, 1-piperazinyl, morpholino, and the like), and the othersymbols have the same meanings as above.)Step I:

Compound (75) can be prepared by reacting Compound (72), which can beobtained by reacting benzotriazole with a cyanogen halide (such ascyanogen bromide), with Compound (73) in an appropriate solvent in thepresence of a base, followed by reaction with Compound (74) in anappropriate solvent in the presence of a base.

As the solvent in the reaction of Compound (72) with Compound (73),ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbonssuch as methylene chloride, acetonitrile, and the like can be used.

As the base in the reaction of Compound (72) with Compound (73), anorganic base such as triethylamine, diisopropylethylamine and pyridinecan be used.

The reaction time in the reaction of Compound (72) with Compound (73) isusually 1 hour to 24 hours, preferably 3 hours to 12 hours. The reactiontemperature is usually 0 to 40° C., preferably 0 to 25° C.

As the solvent in the reaction with Compound (74), halogenatedhydrocarbons such as chloroform and methylene chloride, ethers such astetrahydrofuran and dioxane, halogenated hydrocarbons such as methylenechloride, acetonitrile, and the like can be used.

As the base in the reaction with Compound (74), an organic base such astriethylamine, diisopropylethylamine and pyridine can be used.

The reaction time in the reaction with Compound (74) is usually 1 hourto 24 hours, preferably 1 hour to 12 hours. The reaction temperature isusually 0 to 60° C., preferably 0 to 40° C.

Step II:

Compound (76) can be prepared by reacting Compound (75) with hydrazinein an appropriate solvent according to a method as described inSynthesis, 2001, 6, 897-903.

As the solvent, halogenated hydrocarbons such as chloroform andmethylene chloride, and the like can be used.

The reaction time is usually 1 hour to 24 hours, preferably 3 hour to 12hours. The reaction temperature is usually 0 to 60° C., preferably 0 to40° C.

Step III:

Compound (41f) can be prepared by protecting Compound (76) in a mannersimilar to Step III of Method X.

[Method AD]

Compound (41) wherein R^(2b) is aromatic hydrocarbon group which may besubstituted (hereinafter, referred to as Compound (41g)) can be preparedby the process as below:

(wherein R^(2b7) represents aromatic hydrocarbon group which may besubstituted, and the other symbols have the same meanings as above.)

Compound (41g) can be prepared by reacting Compound (68) with Compound(77) in an appropriate solvent in the presence of a base, and byprotecting the amino group with PG₃.

As the solvent, alcohols such as methanol, ethanol and isopropylalcohol,and the like can be used.

As the base, an alkali metal alkoxide such as sodium methoxide andpotassium methoxide, and the like can be used.

The reaction time is usually 12 hours to 72 hours, preferably 24 hoursto 48 hours. The reaction temperature is usually 25 to 100° C.,preferably 50 to 90° C.

[Method AE]

Compound (41) wherein R^(2b) is alkyl which may be substituted,cycloalkyl which may be substituted, or aromatic hydrocarbon group whichmay be substituted (hereinafter, referred to as Compound (41h)) can beprepared by the process as below:

(wherein each symbol has the same meaning as above.)

Compound (79) can be prepared by reacting Compound (58) with Compound(78) in an appropriate solvent under oxygen atmosphere in the presenceof a base and a catalyst according to a method as described in J. Am.Chem. Soc. 2009, 131, p. 15080-15081.

As the solvent, dimethylsulfoxide, N, N-dimethyformamide,dichlorobenzene, toluene, and the like can be used.

As the base, an alkali metal carbonate such as sodium carbonate,potassium carbonate and cesium carbonate, and the like can be used.

As the catalyst, a catalyst such as copper (I) chloride, copper (I)bromide, copper (II) bromide, copper (II) acetate can be used. Dependingon the reactive group, 1,10-phenanthroline and zinc (II) halide iseffective as an additive.

The reaction time is usually 12 hours to 48 hours, preferably 12 hoursto 24 hours. The reaction temperature is usually room temperature to thereflux temperature of the solvent, preferably 80 to 150° C.

Step II:

A reaction from Compound (79) to Compound (41h) can be carried out in amanner similar to Step III of Method X.

[Method AF]

Compound (46) and Compound (49a) which is Compound (49) wherein LV¹⁰ istrifluoromethanesulfonyloxy can be prepared by the process as below:

(wherein PG₄ represents a hydroxyl group-protective group (preferably,benzyl and the like), and the other symbols have the same meanings asabove.)Step I:

The coupling reaction of Compound (41) with Compound (80) can be carriedout in a manner similar to Step I of Method R.

Step II:

Compound (46) can be prepared by deprotecting PG₄ of Compound (81).

The deprotection reaction of PG₄ can be carried, for example when PG₄ isbenzyl group, by subjecting Compound (81) to a hydrogenation reaction inan appropriate solvent (alcohols such as methanol and ethanol, and thelike) in the presence of palladium catalyst (such as palladium carbonand palladium hydroxide) under hydrogen atmosphere to prepare Compound(46).

Step III:

Compound (49a) can be prepared by reacting Compound (46) withtrifluoromethanesulfonic anhydride in an appropriate solvent(halogenated hydrocarbons such as methylene chloride and chloroform,ethers such as tetrahydrofuran and dimethyl ether, and the like) in thepresence of a base (such as triethylamine and N,N-diisopropylethylamine)at 0° C. to 25° C. for 1 hour to 8 hours.

The compound represented by the general formula (A) can be prepared bythe above Method A to Method AF, or according to a method as describedin PCT/JP2011/079958.

When the compound of the present invention, the intermediate compound,the starting compound, and the like have a functional group (such ashydroxyl, amino and carboxy), the functional group can be protected witha protective group which is usually used in the organic syntheticchemistry and after a reaction, the protective group can be removed toobtain an intended compound, according to a method as described inTheodora W. Greene, Peter G. M. Wuts, “Protective Groups in OrganicSynthesis” 3rd. ed., John Wiley & Sons, Inc., 1999. As the protectivegroup, a protective group which is usually used in the organic syntheticchemistry described in the above book can be mentioned, and as aprotective group of hydroxyl group, for example, tetrahydropyranyl,trimethylsilyl, t-butyldimethylsilyl, benzyl, 4-methoxybenzyl,methoxymethyl, acetyl, and the like can be mentioned. As a protectivegroup of amino group, for example, t-butoxycarbonyl, benzyloxycarbonyl,9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,t-amyloxycarbonyl, 4-methoxybenzyl, 2-nitrobenzenesulfonyl,2,4-dinitrobenzenesulfonyl, 2-(trimethylsilyl)ethoxymethyl, and the likecan be mentioned, and as a protective group of carboxy, for example,alkyl such as methyl, ethyl and t-butyl, benzyl, and the like can bementioned.

Further, after the compound of the present invention or the intermediatecompound is prepared by the above method, the functional group can beconverted or modified according to an ordinary method. The specificmethods can be mentioned as follows.

(1) Conversion of Carboxy or Ester Thereof to Aminocarbonyl

By converting a carboxy or a salt thereof to an acyl halide and reactingit with an amine; by reacting a carboxy or a salt thereof with an aminein the presence of a condensation agent; or by reacting an ester thereofwith an amine, a carboxy or ester thereof can be converted to acorresponding aminocarbonyl.(2) Conversion of Amine to Amide

By reacting an amine or a salt thereof with a carboxy or a correspondingacyl halide; by reacting an amine or a salt thereof with a carboxy inthe presence of a condensing agent; or by reacting an amine with anester of carboxy, an amine can be converted to a corresponding amide.

(3) Conversion of Ester to Carboxy

By hydrolyzing an ester with an alkali metal hydroxide base (such assodium hydroxide and potassium hydroxide) or an acid (such ashydrochloric acid and sulfuric acid); or by hydrogenating using a metalcatalyst, an ester can be converted to a corresponding carboxy or a saltthereof can be obtained.

(4) Conversion of Ester to Hydroxymethyl

By reacting an ester with a reducing agent (such as metal reducing agentincluding sodium borohydride, lithium borohydride, lithium aluminiumhydride and sodium triacetoxyborohydride), an ester can be converted toa corresponding hydroxymethyl.

(5) Conversion of Alcohol to Ether

By reacting an alcohol with an alkyl halide in the presence of a base,an alcohol can be converted to a corresponding ether.

(6) Conversion of Alcohol to Aldehyde

By reacting an alcohol with an oxidizing agent (such as manganesedioxide), an alcohol can be converted to a corresponding aldehyde.

(7) Conversion of Aldehyde to Aminomethyl or Cyclic Aminomethyl

By reacting an aldehyde with an amine or a cyclic amine (such aspiperidine, piperazine and morpholine) in the presence of a reducingagent (such as metal reducing agent including sodium borohydride,lithium borohydride, lithium aluminium hydride and sodiumtriacetoxyborohydride), an aldehyde can be converted to a correspondingaminomethyl or cyclic aminomethyl.

(8) Conversion of Halogen to Cyano

By reacting a halogen with a cyanating agent (such as potassiumhexacyanoferrate (II) trihydrate, copper (I) cyanide and zinc cyanide) apalladium catalyst (such as palladium acetate and PdCl₂(dppf)), a ligand(such as butyl di-1-adamantylphosphine, X-PHOS, S-PHOS and Xantphos),and in the presence or absence of a base (such as sodium carbonate andpotassium carbonate), a halogen can be converted to a correspondingcyano.

(9) Conversion of Haloalkyl to Carboxy

By hydrolyzing a haloalkyl with a base (such as an alkali metalhydroxide base including sodium hydroxide and potassium hydroxide), ahaloalkyl can be converted to a corresponding carboxy or a salt thereof.

(10) Conversion of Haloalkyl to Cyano

By treating a haloalkyl with ammonia, a haloalkyl can be converted to acorresponding cyano or a salt thereof.

(11) Conversion of Alkylthio to Alkylsulfonyl

By treating an alkylthio with an oxidizing agent (such asm-chloro-perbenzoic acid), an alkylthio can be converted to acorresponding alkylsulfonyl.

(12) Conversion of Alkylsulfonyl to Alkoxy, Aryloxy or Heteroaryloxy

By reacting an alkylsulfonyl with an alcohol, a hydroxyaryl or ahydroxyheteroaryl in the presence of a base (such as potassiumcarbonate, sodium carbonate and sodium hydride), an alkylsulfonyl can beconverted to a corresponding alkoxy, aryloxy, or heteroaryloxy.

Further, the prepared compound of the present invention and eachintermediate compound in the above preparation can be purified by anordinary method, for example, chromatography, distillation,recrystallization, and the like. As the solvent for recrystallization,for example, an alcohol solvent such as methanol, ethanol and2-propanol; an ether solvent such as diethylether, diisopropylether andTHF; an ester solvent such as ethyl acetate; an aromatic solvent such astoluene; a ketone solvent such as acetone; a hydrocarbon solvent such ashexane; water, and the like; or a solvent mixture thereof; and the likecan be mentioned. Further, the compound of the present invention can beconverted to a pharmaceutically acceptable salt thereof according to anordinary method, and then, recrystallization and the like can be carriedout.

If the compound of the present invention or a pharmaceuticallyacceptable salt thereof has an optical isomer based on an asymmetriccarbon, they can be separated to each optical isomer by an ordinaryoptical resolution method (fractional crystallization method orseparation method using a chiral column) Further, an optically purestarting compound can be used to synthesize an optical isomer.

Effect of the Invention

The compound of the present invention or a pharmaceutically acceptablesalt thereof has an excellent DGAT1 inhibitory activity, and is usefulas a medicament for the prevention and/or treatment of the followingdiseases in warm-blooded animals, preferably, mammals including humanbeing:

(1) diseases relating to adiposity (obesity): hyperlipidemia,hypertriglyceridemia, lipid metabolism disorder, fatty liver, and thelike,

(2) diseases considered to be caused by adiposity (obesity); type 2diabetes mellitus, diabetic complication (including diabetic peripheralneuropathy, diabetic nephropathy, diabetic retinopathy and diabeticmacroangiopathy); arteriosclerosis, hypertension, cerebrovasculardisorder, coronary artery disease; dyspnoea, lumbago, gonarthrosis, andthe like, and(3) familial hyperchylomicronemia.

Further, since the compound of the present invention or apharmaceutically acceptable salt thereof has GLP-1 secretion promotingactivity based on DGAT1 inhibitory activity, it is expected to haveinsulin secretion promoting activity, and/or a pancreas-protectingactivity.

Thus obtained compound of the present invention or a pharmaceuticallyacceptable salt thereof can be formulated as a pharmaceuticallycomposition comprising a therapeutically effective amount of thecompound and a pharmaceutically acceptable carrier. As thepharmaceutically acceptable carrier, a binder (for example,hydroxypropylcellulose, polyvinylalcohol, polyvinylpyrrolidone, orpolyethyleneglycol), excipient (for example, lactose, sucrose, mannitol,sorbitol, cornstarch, potato starch, crystalline cellulose or calciumcarbonate), a lubricant (for example, magnesium stearate, calciumstearate or talc), a disintegrating agent (for example, low substitutedhydroxypropylcellulose, or cross-linked carboxymethylcellulose), ahumectant (for example, sodium lauryl sulfate), and the like can bementioned.

The compound of the present invention or a pharmaceutically acceptablesalt thereof can be orally or parenterally administered, and can be usedas an appropriate pharmaceutical preparation. As an appropriatepharmaceutical preparation for oral administration, for example, a solidpreparation such as tablet, granule, capsule, or powder; a solutionpreparation, a suspension preparation, and an emulsion preparation canbe mentioned. As an appropriate pharmaceutical preparation forparenteral administration, suppository, injection or drip infusionpreparation using distilled water for injection, physiological saline,glucose aqueous solution, and the like; inhalant, and the like can bementioned.

The dose of the compound of the present invention or a pharmaceuticallyacceptable salt thereof, differs depending on the administration method;the age, the body weight and the condition of patient, and it is 0.001to 100 mg/kg/day, preferably 0.1 to 30 mg/kg/day, more preferably 0.1 to10 mg/kg/day for usual oral administration, which is administered in onedose or in 2 to 4 doses. For parenteral administration, 0.0001 to 10mg/kg/day is preferable, which is administered in one dose or severaldoses. Further, for transmucosal administration, 0.001 to 100 mg/kg/dayis administered once a day or in several doses.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained in detail hereinafter with examples,reference examples and experimental examples, but, the present inventionis not limited thereby.

EXAMPLE Example 1-1

(1) An acetate of Compound 1 (1.94 g) and potassium carbonate (1.73 g)were dissolved in dichloromethane (50 mL) and saturated brine (50 mL),to this was added Compound 2 (phenacyl bromide) (1.49 g), and then themixture was heated at reflux for 4 hours. After the temperature of thereaction solution was brought back to room temperature, dichloromethanewas added to carry out a liquid separation. The organic layer wasseparated and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (chloroform:methanol=99:1 to 95:5),to the obtained residue was added diethyl ether, the solid was collectedby filtration, washed with diethyl ether and dried to obtain Compound 3(1.93 g).

MS (m/z): 428 [M+H]⁺

(2) Compound 3 (0.31 g) was dissolved in methanol (7 mL) andtetrahydrofuran (7 mL), and an 8N aqueous sodium hydroxide solution(0.92 mL) was added dropwise, and the mixture was stirred at 50° C.overnight. After the temperature of the reaction solution was broughtback to room temperature, the solvent was distilled off under reducedpressure, and to the obtained residue was added water, and the mixturewas neutralized with acetic acid. After the solvent was distilled underreduced pressure, water was added, and the obtained solid residue wascollected by filtration, washed with water and subsequently dried. Tothe obtained residue was added diethyl ether, and the solid wascollected by filtration, washed with diethyl ether and dried to obtainCompound 4 (0.29 g).

MS (m/z): 414 [M+H]⁺

Examples 1-2 to 1-69

A treatment was carried out in a manner similar to the Example 1-1 toobtain compounds of Examples 1-2 to 1-69 in Table 1 below.

TABLE 1 Example Starting material 1 Starting material 2 1-2 

1-3 

1-4 

1-5 

1-6 

1-7 

1-8 

1-9 

1-10

1-11

1-12

1-13

1-14

1-15

1-16

1-17

1-18

1-19

1-20

1-21

1-22

1-23

1-24

1-25

1-26

1-27

1-28

1-29

1-30

1-31

1-32

1-33

1-34

1-35

1-36

1-37

1-38

1-39

1-40

1-41

1-42

1-43

1-44

1-45

1-46

1-47

1-48

1-49

1-50

1-51

1-52

1-53

1-54

1-55

1-56

1-57

1-58

1-59

1-60

1-61

1-62

1-63

1-64

1-65

1-66

1-67

1-68

1-69

Example Product MS (m/z) 1-2 

432 [M + H]⁺ 1-3 

432 [M + H]⁺ 1-4 

432 [M + H]⁺ 1-5 

450 [M + H]⁺ 1-6 

450 [M + H]⁺ 1-7 

450 [M + H]⁺ 1-8 

450 [M + H]⁺ 1-9 

448/450 [M + H]⁺ 1-10

448/450 [M + H]⁺ 1-11

482 [M + H]⁺ 1-12

482 [M + H]⁺ 1-13

482 [M + H]⁺ 1-14

498 [M + H]⁺ 1-15

444 [M + H]⁺ 1-16

444 [M + H]⁺ 1-17

488 [M + H]⁺ 1-18

472 [M + H]⁺ 1-19

474 [M + H]⁺ 1-20

474 [M + H]⁺ 1-21

474 [M + H]⁺ 1-22

500 [M + H]⁺ 1-23

512 [M + H]⁺ 1-24

480 [M + H]⁺ 1-25

498 [M + H]⁺ 1-26

458 [M + H]⁺ 1-27

415 [M + H]⁺ 1-28

429 [M + H]⁺ 1-29

415 [M + H]⁺ 1-30

415 [M + H]⁺ 1-31

416 [M + H]⁺ 1-32

483 [M + H]⁺ 1-33

483 [M + H]⁺ 1-34

420 [M + H]⁺ 1-35

421 [M + H]⁺ 1-36

418 [M + H]⁺ 1-37

419 [M + H]⁺ 1-38

414 [M + H]⁺ 1-39

444 [M + H]⁺ 1-40

498 [M + H]⁺ 1-41

428 [M + H]⁺ 1-42

458 [M + H]⁺ 1-43

512 [M + H]⁺ 1-44

428 [M + H]⁺ 1-45

458 [M + H]⁺ 1-46

442 [M + H]⁺ 1-47

472 [M + H]⁺ 1-48

526 [M + H]⁺ 1-49

459 [M + H]⁺ 1-50

429 [M + H]⁺ 1-51

446 [M + H]⁺ 1-52

476 [M + H]⁺ 1-53

447 [M + H]⁺ 1-54

416 [M + H]⁺ 1-55

444 [M + H]⁺ 1-56

428 [M + H]⁺ 1-57

442 [M + H]⁺ 1-58

458 [M + H]⁺ 1-59

496 [M + H]⁺ 1-60

527 [M + H]⁺ 1-61

427 [M + H]⁺ 1-62

457 [M + H]⁺ 1-63

511 [M + H]⁺ 1-64

444 [M + H]⁺ 1-65

433 [M + H]⁺ 1-66

432 [M + H]⁺ 1-67

461 [M + H]⁺ 1-68

461 [M + H]⁺ 1-69

483 [M + H]⁺

Example 2-1

Compound 1 (4.40 g) was suspended in acetonitrile (100 mL), and a 1Naqueous sodium hydroxide solution (10.6 mL) was added dropwise, and themixture was stirred at room temperature overnight. The obtained solidwas collected by filtration, washed with acetonitrile and subsequentlydried to obtain Compound 2 (4.55 g).

MS (m/z): 412 [M−Na]⁻

Examples 2-2 to 2-16

A treatment was carried out in a manner similar to the Example 2-1 toobtain compounds of Examples 2-2 to 2-16 in Table 2 below.

TABLE 2 Ex- am- MS ple Starting material Product (m/z) 2-2 

496 [M − Na]⁻ 2-3 

478/480 [M − Na + Cl]⁻ 2-4 

478 [M − Na]⁻ 2-5 

496 [M − Na]⁻ 2-6 

456 [M − Na]⁻ 2-7 

412 [M − Na]⁻ 2-8 

442 [M − Na]⁻ 2-9 

496 [M − Na]⁻ 2-10

426 [M − Na]⁻ 2-11

456 [M − Na]⁻ 2-12

508/510 [M + Cl − Na]⁻ 2-13

486 [M − Na]⁻ 2-14

480 [M − Na]⁻ 2-15

508/510 [M + Cl − Na]⁻ 2-16

442 [M − Na]⁻

Example 3-1

(1) Compound 1 (300 mg), Compound 2 (163 mg) and potassium carbonate(308 mg) were added into tetrahydrofuran (8 mL), and additionallysaturated brine (8 mL) was added, and the mixture was stirred at 80° C.for 3 hours. After the reaction solution was cooled to room temperature,ethyl acetate and saturated brine were added to carry out a liquidseparation. The organic layer was separated and subsequently dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. To the obtained residue was added acetic acid (8 mL),and the mixture was stirred at 80° C. for 2 hours. After the temperatureof the reaction solution was brought back to room temperature, thesolvent was distilled off under reduced pressure, and ethyl acetate andsaturated brine were added to carry out a liquid separation. The organiclayer was separated and subsequently dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(chloroform:methanol=100:0 to 97:3) to obtain Compound 3 (144 mg).

MS (m/z) 444 [M+H]⁺

(2) Compound 3 (142 mg) was treated in a manner similar to the Example1-1 (2) to obtain Compound 4 (115 mg).

MS (m/z): 430 [M+H]⁺

Examples 3-2 to 3-13

A treatment was carried out in a manner similar to the Example 3-1 toobtain compounds of Examples 3-2 to 3-13 in Table 3 below.

TABLE 3 Example Starting material 1 Starting material 2 3-2 

3-3 

3-4 

3-5 

3-6 

3-7 

3-8 

3-9 

3-10

3-11

3-12

3-13

Example Product MS (m/z) 3-2 

514 [M + H]⁺ 3-3 

446 [M + H]⁺ 3-4 

500 [M + H]⁺ 3-5 

445 [M + H]⁺ 3-6 

475 [M + H]⁺ 3-7 

529 [M + H]⁺ 3-8 

414 [M + H]⁺ 3-9 

444 [M + H]⁺ 3-10

498 [M + H]⁺ 3-11

428 [M + H]⁺ 3-12

458 [M + H]⁺ 3-13

512 [M + H]⁺

Example 4-1

(1) Compound 1 (250 mg) and Compound 2 (105 mg) were treated in a mannersimilar to the Example 1-1 (1) to obtain Compound 3 (131.9 mg).

MS (m/z): 503 [M+H]⁺

(2) Compound 3 (130 mg) was dissolved in trifluoroacetic acid (3 mL) andwater (0.3 mL), and the mixture was stirred at room temperature for 3hours. The residue obtained by concentration under reduced pressure wasdissolved in tetrahydrofuran, and the mixture was neutralized with a 1Naqueous sodium hydroxide solution. After a few drops of acetic acid wasadded, ethyl acetate and water were added to carry out a liquidseparation. The organic layer was separated and subsequently dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. To the obtained residue were added diethyl ether,diisopropyl ether and ethyl acetate, the mixture was powderized and thesolvent was distilled off under reduced pressure. To the obtainedresidue was added diisopropyl ether, and the powder was collected byfiltration and dried to obtain Compound 4 (94.5 mg).

MS (m/z) 447 [M+H]⁺

Examples 4-2 to 4-16

A treatment was carried out in a manner similar to the Example 4-1 toobtain compounds of Examples 4-2 to 4-16 in Table 4 below.

TABLE 4 Example Starting material 1 Starting material 2 4-2 

4-3 

4-4 

4-5 

4-6 

4-7 

4-8 

4-9 

4-10

4-11

4-12

4-13

4-14

4-15

4-16

MS Example Product (m/z) 4-2 

477 [M + H]⁺ 4-3 

442 [M + H]⁺ 4-4 

472 [M + H]⁺ 4-5 

526 [M + H]⁺ 4-6 

459 [M + H]⁺ 4-7 

489 [M + H]⁺ 4-8 

458 [M + H]⁺ 4-9 

488 [M + H]⁺ 4-10

441 [M + H]⁺ 4-11

471 [M + H]⁺ 4-12

428 [M + H]⁺ 4-13

458 [M + H]⁺ 4-14

512 [M + H]⁺ 4-15

444 [M + H]⁺ 4-16

474 [M + H]⁺

Example 5-1

Compound 1 (300 mg), Compound 2 (187 mg) and potassium carbonate (308mg) were added to tetrahydrofuran (8 mL), and additionally saturatedbrine (8 mL) was added, and the mixture was stirred at 80° C. for 5hours. After the reaction solution was cooled to room temperature, ethylacetate and saturated brine were added to carry out a liquid separation.The organic layer was separated and dried over anhydrous sodium sulfate,and subsequently the solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography(chloroform:methanol=100:0 to 94:6). The obtained solid was dissolved inmethanol (5 mL) and tetrahydrofuran (5 mL), and a 2N aqueous sodiumhydroxide solution (1.52 mL) was added, and the mixture was stirred at50° C. for 3 hours. To the residue obtained by concentration underreduced pressure were added water and acetic acid, and the depositedsolid was washed with water and dried to obtain Compound 3 (117.2 mg).

MS (m/z) 460 [M+H]⁺

Example 5-2

A treatment was carried out in a manner similar to the Example 5-1 toobtain a compound of Example 5-2 in Table 5 below.

TABLE 5 Example Starting material 1 Starting material 2 5-2

MS Example Product (m/z) 5-2

498 [M + H]⁺

Example 6

(1) Compound 1 (696 mg) and Compound 2 (665 mg) were treated in a mannersimilar to Example 1-1 (1) to obtain Compound 3 (938 mg).

MS (m/z): 562 [M+H]⁺

(2) Compound 3 (936 mg) was dissolved in N,N-dimethylformamide (9 mL),and 60% sodium hydride (87 mg) was added under a nitrogen atmosphereunder ice cooling, and the mixture was stirred. After 1 hour,2-(trimethylsilyl)ethoxymethyl chloride (442 μL) was added under icecooling, and the mixture was stirred overnight while the temperaturegradually brought back to room temperature. To the reaction solution wasadded a saturated aqueous ammonium chloride solution, and a liquidseparation was carried out between ethyl acetate and water. The organiclayer was dried over anhydrous sodium sulfate and subsequently thesolvent was distilled off under reduced pressure. The obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=85:15 to 65:35) to obtain Compound 4 (782 mg).

MS (m/z): 692 [M+H]⁺

(3) Compound 4 (782 mg) was dissolved in methanol (15 mL) andtetrahydrofuran (15 mL), 10% palladium carbon (300 mg) was added under anitrogen atmosphere and subsequently a hydrogen atmosphere wassubstituted therefor, and the mixture was stirred at room temperaturefor 3 hours. The insoluble substance was filtered through amembrane-filter and the filtrate was concentrated under reduced pressureto obtain Compound 5 (658 mg).

MS (m/z): 602 [M+H]⁺

(4) Compound 5 (655 mg) was dissolved in tetrahydrofuran (13 mL) andtriethylamine (182 μL) and isobutyl chloroformate (169 μL) were addedunder ice cooling, and the mixture was stirred for 30 minutes. Theobtained solid was filtered and washed with tetrahydrofuran, andsubsequently to the filtrate was added sodium borohydride (62 mg) underice cooling, and the mixture was stirred for two days while thetemperature brought back to room temperature. To the reaction solutionwas added a saturated aqueous ammonium chloride solution and a liquidseparation was carried out between ethyl acetate and water. The organiclayer was separated and dried over anhydrous sodium sulfate, andsubsequently the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(chloroform:methanol=100:0 to 95:5) to obtain Compound 6 (553 mg).

MS (m/z): 588 [M+H]⁺

(5) Compound 6 (551 mg) was dissolved in dichloromethane (11 mL) andmanganese dioxide (815 mg) was added, and the mixture was stirred atroom temperature overnight. The insoluble substance was filtered througha membrane-filter, and the filtrate was concentrated under reducedpressure to obtain Compound 7 (443 mg).

MS (m/z): 586 [M+H]⁺

(6) Compound 7 (441 mg) was dissolved in tetrahydrofuran (9 mL) andmorpholine (132 μL) was added, and the mixture was stirred. After 1hour, sodium triacetoxyborohydride (479 mg) and acetic acid (43 μL) wereadded, and the mixture was further stirred at room temperatureovernight. Dichloromethane and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction solution to carry out aliquid separation. The organic layer was washed with water, and driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=50:50 to 0:100) to obtainCompound 8 (477 mg).

MS (m/z): 657 [M+H]⁺

(7) Compound 8 (475 mg) was dissolved in trifluoroacetic acid (10 mL)and water (1 mL), and the mixture was stirred at room temperatureovernight. After the solvent was distilled off under reduced pressure,ethyl acetate and a saturated aqueous sodium hydrogen carbonate solutionwere added to the residue to carry out a liquid separation. The organiclayer was washed with water, and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure. The obtainedresidue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL) anda 2N aqueous sodium hydroxide solution (1.8 mL) was added under icecooling, and the mixture was stirred at room temperature overnight. Tothe reaction solution was added 2N hydrochloric acid (1.8 mL), and thesolvent was distilled off under reduced pressure. The obtained residuewas purified by preparative LC-MS to obtain Compound 9 (264 mg).

MS (m/z): 513 [M+H]⁺

Example 7

(1) Compound 1 (1000 mg), Compound 2 (986 mg) and a[1,1′-bis(diphenylphosphino)ferrocene]palladiumdichloride-dichloromethane complex (193 mg) were dissolved inN,N-dimethylformamide (12 mL), and a 2M aqueous sodium carbonatesolution (3.55 mL) was added, and the mixture was stirred under anitrogen atmosphere at 65° C. for 6 hours. After the reaction solutionwas cooled to room temperature, brine and ethyl acetate were added tocarry out a liquid separation. After the organic layer was separated,anhydrous magnesium sulfate and activated charcoal were added andfiltered through Celite. The filtrate was concentrated under reducepressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=88:12, 80:20 and to 75:25) toobtain Compound 3 (1.14 g).

MS (m/z): 550 [M+H]⁺

(2) Compound 3 (2.56 g) was dissolved in trifluoroacetic acid (40 mL)and water (6 mL), and the mixture was stirred at room temperatureovernight. To the residue obtained by concentration under reducepressure was added a saturated aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate andtetrahydrofuran. The organic layer was washed with saturated brine andsubsequently dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (chloroform:methanol=100:0 to 95:5)to obtain Compound 4 (1.90 g).

MS (m/z): 420 [M+H]⁺

(3) Compound 4 (1.88 g) was dissolved in methanol (20 mL) andtetrahydrofuran (20 mL), and 28% aqueous ammonia (40 mL) was added, andthe mixture was stirred at 40° C. overnight. Further, 28% aqueousammonia (10 mL) was added in two parts, and the mixture was stirred at40° C. overnight. After the temperature of the reaction solution broughtback to room temperature, the solvent was distilled off under reducedpressure, and ethyl acetate, tetrahydrofuran and water were added to theobtained residue to carry out a liquid separation. The organic layer waswashed with saturated brine and subsequently dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The obtained residue was purified with silica gel columnchromatography (chloroform:methanol=100:0 to 96:4) to obtain Compound 5(1.16 g).

MS (m/z): 377 [M+H]⁺

(4) A treatment was carried out in a manner similar to Example 6 (2)using Compound 5 (854 mg) to obtain Compound 6 (1.09 g).

MS (m/z): 507 [M+H]⁺

(5) A treatment was carried out in a manner similar to Reference Example7-1 (4) using Compound 6 (1.08 g) to obtain Compound 7 (1.14 g).

MS (m/z): 540 [M+H]⁺

(6) To Compound 7 (1.14 g) was added acetic anhydride (15 mL), and themixture was stirred at 120° C. for 2 hours. After the temperature of thereaction solution brought back to room temperature, the solvent wasdistilled off under reduced pressure (including an azeotropic procedureusing toluene (three times)), to the obtained residue added a saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and the aqueous layer thus obtained was furtherextracted with ethyl acetate. After the organic layers were combined anddried over anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate) to obtain Compound 8 (679 mg).

MS (m/z): 564 [M+H]⁺

(7) A treatment was carried out in a manner similar to the Example 6 (7)using Compound 8 (672 mg) to obtain Compound 9 (389 mg).

MS (m/z): 420 [M+H]⁺

Example 8

(1) Compound 1 (102 mg) and Compound 2 (119 mg) were dissolved indimethylformamide (2.5 mL), and a palladium chloride (dppf)-methylenechloride complex (10 mg) and a 2M aqueous sodium carbonate solution (0.5mL) were added, and the mixture was stirred under a nitrogen atmosphereat 70° C. for 8 hours. Water and ethyl acetate were added to thereaction mixture to carry out a liquid separation, to the organic layerwas added hexane, and the solution was washed with water and saturatedbrine. After the organic layer was dried over anhydrous sodium sulfate,the solvent was distilled off under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=90:10 to 67:33) to obtain Compound 3 (81 mg).

MS (m/z): 582 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 7 (2)using Compound 3 (80 mg) to obtain Compound 4 (51 mg)

MS (m/z): 452 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 4 (43 mg) to obtain Compound 5 (36 mg).

MS (m/z): 438 [M+H]⁺

Example 9

(1) Compound 1 (9.43 g), Compound 2 (10 g) and sodium carbonate (8.77 g)were added to a mixed solvent of toluene (285 mL), ethanol (143 mL) andwater (143 mL), and the atmosphere was replaced with a nitrogenatmosphere. To this was added tetrakistriphenylphosphine palladium (0.48g), and the mixture was heated at reflux for 16 hours. After thereaction solution was cooled to room temperature, ethyl acetate andwater were added to carry out a liquid separation. The organic layer wasseparated and dried over anhydrous magnesium sulfate, and subsequentlythe solvent was distilled off under reduced pressure. The obtained solidwas crystallized from ethyl acetate to obtain Compound 3 (10.55 g).

MS (m/z): 340/342 [M+H]⁺

(2) Compound 3 (1000 mg), bis(pinacolato)diborane (933 mg) and potassiumacetate (865 mg) were added to 1,4-dioxane (29 mL), and the mixture wassubjected to nitrogen substitution. To this were added a palladiumchloride (dppf)-methylene chloride complex (72 mg) and dppf (49 mg) andthen nitrogen substitution was carried out, and the mixture was stirredat 80° C. overnight. To the reaction solution were added water and ethylacetate, and the mixture was stirred, and filtered through Celite. Theorganic layer was separated, and anhydrous magnesium sulfate andactivated charcoal were added, and the mixture was filtered throughCelite. The solvent was distilled off under reduced pressure. To theobtained residue was added methanol, and the solid was collected byfiltration to obtain Compound 4 (803 mg).

MS (m/z): 388 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 6 (2)using Compound 5 (10 g) to obtain a mixture of Compound 6 and Compound 7(13.27 g).

MS (m/z): 423/425 [M+H]⁺

(4) Compound 4 (800 mg) and the mixture of Compound 6 and Compound 7(1139 mg) were added to a mixed solvent of a 2M aqueous sodium carbonatesolution (4131 μL) and dimethoxyethane (17 mL), and the mixture wassubjected to nitrogen substitution. To this was addedtetrakis(triphenylphosphine)palladium (24 mg), and the mixture wasstirred at 80° C. for 12 hours. To the reaction solution were addedethyl acetate and water, and the mixture was stirred. The insolublesubstance was filtered out. The organic layer was separated, washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=91:9 to 67:33) to obtain a mixture of Compound 8 and Compound 9(749 mg).

MS (m/z): 604/606 [M+H]⁺

(5) A mixture of Compound 8 and Compound 9 (500 mg), phenylboronic acid(151 mg) and a 2M aqueous sodium carbonate solution (1654 μL) were addedto a mixed solvent of dimethoxyethane (5 mL) and ethanol (5 mL), and themixture was subjected to nitrogen substitution. To this was added apalladium chloride (dppf)-methylene chloride complex (68 mg), and themixture was stirred at 80° C. overnight. Ethyl acetate and water wereadded to the reaction solution to carry out a liquid separation. Theorganic layer was separated and washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=90:10 to 85:15) to obtain amixture of Compound 10 and Compound 11 (403 mg).

MS (m/z): 602 [M+H]⁺

(6) The mixture of Compound 10 and Compound 11 (400 mg) was dissolved inmethanol (8 mL), and palladium-carbon (80 mg) was added, and the mixturewas stirred under a hydrogen atmosphere at room temperature for 5 hours.The insoluble matter was filtered through a membrane-filter, and thefiltrate was concentrated under reduced pressure to obtain a mixture ofCompound 12 and Compound 13 (300 mg).

MS (m/z): 512 [M+H]⁺

(7) A treatment was carried out in a manner similar to Reference Example7-1 (1) using the mixture of Compound 12 and Compound 13 (300 mg) toobtain a mixture of Compound 14 and Compound 15 (58 mg).

MS (m/z): 626 [M+H]⁺

(8) A treatment was carried out in a manner similar to the Example 1-1(2) using the mixture of Compound 14 and Compound 15 (58 mg) to obtain amixture of Compound 16 and Compound 17 (57 mg).

MS (m/z): 612 [M+H]⁺

(9) A treatment was carried out in a manner similar to the Example 7 (2)using the mixture of Compound 16 and Compound 17 (57 mg) to obtainCompound 18 (34 mg).

MS (m/z): 482 [M+H]⁺

Example 10

(1) A treatment was carried out in a manner similar to the Example 7 (1)using Compound 1 (6.69 g) and Compound 2 (6.04 g) to obtain Compound 3(6.54 g).

MS (m/z): 622 [M+H]⁺

(2) Compound 3 (1.14 g) was dissolved in tetrahydrofuran (30 mL), andlithium aluminum hydride (104 mg) was added under ice cooling, and themixture was stirred at 0° C. for 20 minutes. To the reaction solutionwere added sequentially water (1 mL), a 15% aqueous sodium hydroxidesolution (1 mL) and water (2 mL), and the mixture was stirred under icecooling for 30 minutes. The reaction solution was filtered throughCelite, and the filtrate was concentrated under reduced pressure. Theobtained residue was dissolved in tetrahydrofuran, the pH was adjustedto below 4 with a 10% aqueous citric acid solution, and ethyl acetatewas added to carry out a liquid separation. The organic layer wasseparated and washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The obtained residue was purified by silica gel columnchromatography (chloroform:methanol=100:0 to 85:15), to the obtainedsolid were added ice-cold ethyl acetate and n-hexane, and the solid wascollected by filtration to obtain Compound 4 (872 mg).

MS (m/z): 518 [M+H]⁺

(3) Compound 4 (290 mg) was dissolved in tetrahydrofuran (10 mL) andN,N-dimethylformamide (10 mL), and 60% sodium hydride (34 mg) was added,and the mixture was sonicated for 1 minute. To this was added benzylbromide (125 mg) at room temperature, and the mixture was furtherstirred at room temperature for 6 hours. Diethyl ether, n-hexane, ethylacetate and water were added to the reaction solution to carry out aliquid separation. The organic layer was separated and washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. To the obtainedresidue were added diisopropyl ether and n-hexane, and the solid wascollected by filtration to obtain Compound 5 (293 mg).

MS (m/z): 608 [M+H]⁺

(4) Compound 5 (290 mg) was dissolved in methylene chloride (8 mL), andtrifluoroacetic acid (4 mL) was added under ice cooling, and the mixturewas stirred for 1 hour under the same conditions. To the reactionmixture was added an aqueous saturated sodium bicarbonate solution tomake it basic (>pH 8), and a liquid separation was carried out byaddition of ethyl acetate. The organic layer was separated and washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure. The obtainedresidue was purified by silica gel column chromatography(chloroform:methanol=100:0 to 90:10), to the obtained residue were addeddiisopropyl ether and n-hexane, and the solid was collected byfiltration to obtain Compound 6 (209 mg).

MS (m/z): 488 [M+H]⁺

(5) A treatment was carried out in a manner similar to Reference Example7-1 (1) using Compound 6 (208 mg) and Compound 7 (113 mg) to obtainCompound 8 (127 mg).

MS (m/z): 602 [M+H]⁺

(6) A treatment was carried out in a manner similar to Example 7 (2)using Compound 8 (127 mg) to obtain Compound 9 (67 mg).

MS (m/z): 472 [M+H]⁺

(7) A treatment was carried out in a manner similar to Example 1-1 (2)using Compound 9 (67 mg) to obtain Compound 10 (34 mg).

MS (m/z): 458 [M+H]⁺

Example 11

(1) Compound 1 (2.46 g) was dissolved in a mixed solvent ofN,N-dimethylformamide (10 mL) and tetrahydrofuran (20 mL), and 60%sodium hydride (276 mg) was added under ice cooling. After the reactionsolution was stirred for 5 minutes, to this solution was added benzylbromide (1.18 g), and the solution was further stirred under ice coolingfor 2 hours. To the reaction solution was added a 10% aqueous citricacid solution to adjust the pH to 4, and diethyl ether was added tocarry out a liquid separation. The organic layer was separated andwashed with water and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(chloroform:ethyl acetate=100:0 to 85:15) to obtain Compound 2 (2.82 g).

MS (m/z): 518 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 2 (2.82 g) to obtain Compound 3 (2.58 g).

MS (m/z): 504 [M+H]⁺

(3) Compound 3 (200 mg), Compound 4 (83 mg), 1-hydroxybenzotriazole (107mg), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride(152 mg) were added to N,N-dimethylformamide, and the mixture wasstirred at room temperature for two days. The solvent was distilled offunder reduced pressure, and ethyl acetate and a saturated aqueous sodiumhydrogen carbonate solution were added to the obtained residue to carryout a liquid separation. The organic layer was separated, and washedwith a 10% aqueous citric acid solution, water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (chloroform:methanol=100:0 to 85:15) to obtain Compound 5(119 mg).

MS (m/z): 591 [M+H]⁺

(4) Compound 5 (115 mg) was dissolved in tetrahydrofuran (10 mL), and20% palladium hydroxide-carbon (130 mg) was added, and the mixture wasstirred under a hydrogen atmosphere at room temperature for 8 hours. Thesolvent was substituted with ethanol (10 mL), and the mixture wasstirred under a hydrogen atmosphere at 75° C. for 4 hours. The reactionsolution was subject to nitrogen gas substitution, subsequently dilutedwith chloroform and methanol, and filtered. The solvent was distilledoff under reduced pressure, the obtained residue was purified by silicagel column chromatography (chloroform:methanol=100:0 to 85:15), theobtained oil was solidified with diethyl ether and diisopropyl ether,and the obtained solid was collected by filtration to obtain Compound 6(36 mg).

MS (m/z): 501 [M+H]⁺

Example 12

(1) Compound 1 (see Compound 3 in Example 1-1) (200 mg) andN-chlorosuccinimide (102 mg) were added to chloroform (30 mL), and themixture was stirred at room temperature overnight. AdditionalN-chlorosuccinimide (102 mg) was added, and the mixture was furtherstirred for 4 hours. The reaction solution was purified by silica gelcolumn chromatography (chloroform:ethyl acetate=100:0 to 50:50), and theobtained oil was solidified with diisopropyl ether, and diluted withn-hexane. Subsequently, the solid was collected by filtration to obtainCompound 2 (207 mg).

MS (m/z): 462/464 [M+H]⁺

(2) Compound 2 (100 mg), methanol (500 μL), and 60% sodium hydride (26mg) were added to 1,4-dioxane (5 mL), and the mixture was stirred at 95°C. for 1 hour. N,N-Dimethylacetamide (5 mL) was added, and the mixturewas stirred at 95° C. overnight. A 10% aqueous citric acid solution,n-hexane and ethyl acetate were added to the reaction mixture to carryout a liquid separation. The organic layer was separated, washed withwater and saturated brine, dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:ethyl acetate=100:0 to 50:50), and to theobtained solid were added diisopropyl ether and isopropyl alcohol, andfiltered to obtain Compound 3 (51 mg).

MS (m/z): 448/450 [M+H]⁺

Example 13

(1) Compound 1 (250 mg), acetamidine hydrochloride (70 mg), copperbromide (4 mg), and cesium carbonate (482 mg) were added todimethylsulfoxide (4 mL), and the mixture was stirred at 120° C.overnight. To the reaction solution were added water and ethyl acetate,and the mixture was stirred. The insoluble substance was filtered. Theorganic layer of the filtrate was separated, washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (chloroform:methanol=100:0 to90:10), LC-MS preparative, and diol silica gel column chromatography(n-hexane:ethyl acetate=50:50 to 0:100) to obtain Compound 2 (20.4 mg).

MS (m/z): 563 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 6 (7)using Compound 2 (19 mg) to obtain Compound 3 (11.5 mg).

MS (m/z): 419 [M+H]⁺

Example 14

(1) A treatment was carried out in a manner similar to Example 6 (2)using Compound 1 (120 mg) to obtain Compound 2 (112 mg).

MS (m/z): 636/638 [M+H]⁺

(2) Compound 2 (110 mg), K₄[Fe(CN)₆]3H₂O (37 mg), palladium acetate (4mg), butyl di-1-adamantylphosphine (19 mg) and sodium carbonate (4 mg)were added to N-methylpyrrolidone (2 mL), and the mixture was stirredunder a nitrogen atmosphere at 140° C. for 2.5 hours and then at 160° C.for 3 hours. After the reaction solution was cooled to room temperature,ethyl acetate and water were added thereto to carry out a liquidseparation. The organic layer was separated, washed with water andsaturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=90:10 to50:50) to obtain Compound 3 (32 mg).

MS (m/z): 627 [M+H]⁺

(3) To Compound 3 (30 mg) was added a 1M tetrabutylammoniumfluoride-tetrahydrofuran solution (239 μL), and the mixture was stirredat room temperature for 2.5 hours and further 60° C. for 4 hours. Asaturated aqueous sodium hydrogen carbonate solution and ethyl acetatewere added to the reaction solution to carry out a liquid separation.The organic layer was separated, washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was dissolved in methanol (1 mL)a 1N aqueous sodium hydroxide solution (479 μL) was added, and themixture was stirred at room temperature for 17 hours. After 1Nhydrochloric acid (479 μL) was added to the reaction solution, ethylacetate was added to carry out a liquid separation. The organic layerwas separated, washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.After the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 90:10), diethyl etherwas added. The solid was collected by filtration and dried to obtainCompound 4 (13.8 mg).

MS (m/z): 483 [M+H]⁺

Example 15-1

(1) Compound 1 (1394 mg) was dissolved in methanol (14 mL), and sodiummethylate (35 mg) was added, and the mixture was stirred at roomtemperature overnight. To the reaction solution was added ammoniumchloride (377 mg), and the mixture was stirred at room temperature for 1hour and then heated at reflux for 7 hours. The reaction solution wasconcentrated under reduced pressure, to the obtained residue was addedethyl acetate, and the solid was collected by filtration and dried toobtain Compound 2 (1268 mg) as a hydrochloride salt.

MS (m/z): 234/236 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 3-1(1) using Compound 2 (600 mg) and Compound 3 (533 mg) to obtain Compound4 (465 mg).

MS (m/z): 364/366 [M+H]⁺

(3) A treatment was carried out in a manner similar to Example 6 (2)using Compound 4 (450 mg) to obtain Compound 5 (605 mg).

MS (m/z): 494/496 [M+H]⁺

(4) A treatment was carried out in a manner similar to Example 7 (1)using Compound 5 (300 mg) and Compound 6 (253 mg) to obtain Compound 7(88 mg).

MS (m/z): 634/635 [M+H]⁺

(5) A treatment was carried out in a manner similar to Example 6 (7)using Compound 7 (85 mg) to obtain Compound 8 (59 mg).

MS (m/z): 491/493 [M+H]⁺

Example 15-2

A treatment was carried out in a manner similar to the Example 15-1 toobtain a compound of Example 15-2 in Table 6 below.

TABLE 6 Exam- MS ple Starting material Bromoketone Product (m/z) 15-2

461/463 [M + H]⁺

Example 16

Compound 1 (see Reference Example 7-11) (200 mg), Compound 2 (175 mg)and potassium carbonate (242 mg) were added to a mixed solvent ofchloroform (5 mL) and saturated brine (5 mL), and the mixture wasstirred at 70° C. for 7 hours. The organic layer was separated from thereaction solution and dried over anhydrous sodium sulfate, andsubsequently the solvent was distilled off under reduced pressure. Theobtained residue was dissolved in methanol (7 mL) and tetrahydrofuran (7mL), a 2N aqueous sodium hydroxide solution (2186 μL) was added, and themixture was stirred at 50° C. for 5 hours. The reaction solution wasconcentrated under reduced pressure, and to the obtained residue wasadded trifluoroacetic acid (5 mL), and the mixture was stirred at roomtemperature for 7 hours. The reaction solution was concentrated underreduced pressure, and to the obtained residue was added a small amountof tetrahydrofuran, and neutralized with a 1N aqueous sodium hydroxidesolution. After a few drops of acetic acid was added to the reactionsolution, ethyl acetate was added thereto to carry out a liquidseparation. The organic layer was separated and dried over anhydroussodium sulfate, and subsequently the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (chloroform:methanol=100:0 to 94:6), solidified fromdiethyl ether and collected by filtration to obtain Compound 3 (12.3mg).

MS (m/z): 510 [M+H]⁺

Example 17

(1) A treatment was carried out in a manner similar to the Example 7 (1)using a mixture of Compound 1 and Compound 2 (300 mg) and Compound 3(357 mg) to obtain a mixture of Compound 4 and Compound 5 (317 mg).

MS (m/z): 574 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 7 (2)using the mixture of Compound 4 and Compound 5(369 mg) to obtainCompound 6 (235 mg).

MS (m/z): 444 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 6 (195 mg) to obtain Compound 7 (160 mg).

MS (m/z): 430 [M+H]⁺

Example 18-1

(1) A treatment was carried out in a manner similar to the Example 7 (1)using Compound 1 (1.0 g) and Compound 2 (1.08 g) to obtain Compound 3(1.04 g).

MS (m/z): 525 [M+H]⁺

(2) Compound 3 (770 mg) was dissolved in methanol (8 mL) andtetrahydrofuran (6 mL), 10% palladium-carbon (154 mg) was added under anitrogen atmosphere, a hydrogen atmosphere was substituted therefor, andthe mixture was stirred at room temperature for 5 hours. The reactionmixture was filtered through a membrane-filter, and the filtrate wasconcentrated under reduced pressure. The obtained residue was dilutedwith methanol, to this was added activated charcoal, the mixture wasfiltered through Celite, and the filtrate was concentrated under reducedpressure. The residue was crystallized by sonication to obtain Compound4 (612 mg).

MS (m/z): 436 [M+H]⁺

(3) Compound 4 (150 mg), Compound 5 (119 mg) and1,1′-(azodicarbonyl)dipiperidine (ADDP) (217 mg) were mixed intetrahydrofuran (3 mL), to this was added tributylphosphine (213 μL),and the mixture was stirred at 70° C. for 8 hours. Compound 5 (119 mg),1,1′-(azodicarbonyl)dipiperidine (217 mg) and tributylphosphine (213 μL)were additionally added, and the mixture was stirred at 70° C. forfurther 2.5 hours. To the reaction solution was added diethyl ether, andthe insoluble matter was filtered. The filtrate was concentrated underreduced pressure, and purificated by silica gel column chromatography(n-hexane:ethyl acetate=85:15 to 67:33) to obtain Compound 6 (117 mg).

MS (m/z): 590 [M+H]⁺

(4) A treatment was carried out in a manner similar to the Example 7 (2)using Compound 6 (117 mg) to obtain Compound 7 (74 mg).

MS (m/z): 460 [M+H]⁺

(5) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 7 (73 mg) to obtain Compound 8 (27.5 mg).

MS (m/z): 446 [M+H]⁺

Example 18-2

A treatment was carried out in a manner similar to the Example 18-1 toobtain a compound of Example 18-2 in Table 7 below.

TABLE 7 Example Intermediate 1 Intermediate 2 18-2

MS Example Product (m/z) 18-2

446 [M + H]⁺

Example 19-1

(1) A treatment was carried out in a manner similar to the Example 18-1(3) using Compound 1 (100 mg) and Compound 2 (168 mg) to obtain Compound3 (152 mg).

MS (m/z): 662 [M+H]⁺

(2) Compound 3 (151 mg) was dissolved in trifluoroacetic acid (3 mL) andwater (0.3 mL), and the mixture was stirred at room temperatureovernight. The reaction solution was concentrated under reducedpressure, the obtained residue was dissolved in tetrahydrofuran, and0.1N phosphate buffer (pH 7) and ethyl acetate were added to be mixed.The organic layer was separated and concentrated under reduced pressure.To the obtained residue was added cooled methanol, and the solid wascollected by filtration to obtain Compound 4 (89.7 mg).

MS (m/z): 476 [M+H]⁺

Examples 19-2 to 19-4

A treatment was carried out in a manner similar to the Example 19-1 toobtain compounds of Examples 19-2 to 19-4 in Table 8 below.

TABLE 8 Example Intermediate 1 Intermediate 2 19-2

19-3

19-4

MS Example Product (m/z) 19-2

476 [M + H]⁺ 19-3

490 [M + H]⁺ 19-4

477 [M + H]⁺

Example 20-1

(1) A treatment was carried out in a manner similar to the Example 18-1(3) using Compound 1 (200 mg) and Compound 2 (323 mg) to obtain Compound3 (232 mg).

MS (m/z): 652 [M+H]⁺

(2) Compound 3 (230 mg) was dissolved in trifluoroacetic acid (2.3 mL)and water (0.2 mL), and the mixture was stood at room temperature forone day. The reaction solution was concentrated under reduced pressure,and ethyl acetate and a saturated aqueous sodium hydrogen carbonatesolution were added to carry out a liquid separation. The organic layerwas separated, washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.The obtained residue was dissolved in methanol (4.6 mL) andtetrahydrofuran (2.3 mL), 10% palladium-carbon (46 mg) was added, andthe mixture was stirred under a hydrogen atmosphere for 7 hours. Thereaction solution was filtered, the filtrate was concentrated underreduced pressure, and the obtained solid was collected by filtration anddried to obtain Compound 4 (145 mg).

MS (m/z): 432 [M+H]⁺

Example 20-2

A treatment was carried out in a manner similar to the Example 20-1 toobtain a compound of Example 20-2 in Table 9 below.

TABLE 9 Example Intermediate 1 Intermediate 2 20-2

MS Example Product (m/z) 20-2

432 [M + H]⁺

Example 21-1

(1) A treatment was carried out in a manner similar to the Example 18-1(3) using Compound 1 (300 mg) and Compound 2 (343 mg) to obtain Compound3 (438 mg).

MS (m/z): 666 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 18-1(2) using Compound 3 (438 mg) to obtain Compound 4 (260 mg).

MS (m/z): 576 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 7 (2)using Compound 4 (260 mg) to obtain Compound 5 (185 mg) as a racemate.

MS (m/z): 446 [M+H]⁺

Examples 21-2 to 21-4

A treatment was carried out in a manner similar to the Example 21-1 toobtain compounds of Examples 21-2 to 21-4 in Table 10 below.

TABLE 10 Example Intermediate 1 Intermediate 2 21-2

21-3

21-4

MS Example Product (m/z) 21-2

446 [M + H]⁺ 21-3

446 [M + H]⁺ 21-4

446 [M + H]⁺

Example 22

(1) A treatment was carried out in a manner similar to the Example 18-1(3) using Compound 1 (1.55 g) and 4-bromophenol (1.62 g) to obtainCompound 2 (0.408 g).

MS (m/z): 420/422 [M+NH₄]⁺

(2) Compound 2 (400 mg), tris(dibenzylideneacetone)dipalladium(0) (18mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl(X-PHOS) (19 mg), potassium acetate (292 mg) and bis pinacolato diboron(504 mg) were added to 1,4-dioxane (20 mL), and the mixture was heatedat reflux under a nitrogen atmosphere overnight. The reaction solutionwas cooled to room temperature and subsequently filtered through Celite,and the filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=99:1 to 93:7) to obtain Compound 3 (461 mg).

MS (m/z): 468 [M+NH4]⁺

(3) A treatment was carried out in a manner similar to the Example 7 (1)using Compound 3 (460 mg) and Compound 4 (287 mg) to obtain Compound 5(521 mg).

MS (m/z): 666 [M+H]⁺

(4) A treatment was carried out in a manner similar to the Example 18-1(2) and Example 7 (2) using Compound 5 (520 mg) to obtain Compound 6(203 mg).

MS (m/z): 446 [M+H]⁺

Example 23-1

(1) A treatment was carried out in a manner similar to the Example 7 (1)using a mixture of Compound 1 and Compound 2 (1.14 g); and Compound 3(0.8 g) to obtain a mixture of Compound 4 and Compound 5 (749 mg).

MS (m/z): 604/606 [M+H]⁺

(2) A mixture of Compound 4 and Compound 5 (748 mg), methylboronic acid(148 mg) and cesium carbonate (806 mg) were added to 1,4-dioxane (15mL). Under a nitrogen atmosphere, a palladium chloride (dppf)-methylenechloride complex (101 mg) was added, and the mixture was stirred at 80°C. overnight. The reaction solution was cooled to room temperature,subsequently treated with NH-silica gel, and eluted with ethyl acetate.The eluate was concentrated, the obtained residue, methylboronic acid(148 mg) and cesium carbonate (806 mg) were added to 1,4-dioxane (15mL). Under a nitrogen atmosphere, a palladium chloride (dppf)-methylenechloride complex (101 mg) was added, and the mixture was stirred at 80°C. for 2.5 hours. The reaction solution was cooled to room temperature,subsequently treated with NH-silica gel, and eluted with ethyl acetate.The eluate was concentrated, and the obtained residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=90:10 to 70:30)to obtain a mixture of Compound 6 and Compound 7 (579 mg).

MS (m/z): 540 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 18-1(2) using the mixture of Compound 6 and Compound 7 (579 mg) to obtain amixture of Compound 8 and Compound 9 (476 mg).

MS (m/z): 450 [M+H]⁺

(4) A treatment was carried out in a manner similar to the Example 18-1(3) using the mixture of Compound 8 and Compound 9 (161 mg); andCompound 10 (231 mg) to obtain a mixture of Compound 11 and Compound 12(131 mg).

MS (m/z): 676 [M+H]⁺

(5) A treatment was carried out in a manner similar to the Example 19-1(2) using the mixture of Compound 11 and Compound 12 (109 mg) to obtainCompound 13 (39.9 mg).

MS (m/z): 490 [M+H]⁺

Example 23-2

A treatment was carried out in a manner similar to the Example 23-1 toobtain a compound of Example 23-2 in Table 11 below.

TABLE 11 Example Intermediate 1 Intermediate 2 23-2

MS Example Product (m/z) 23-2

420 [M + H]⁺

Example 24-1

(1) A treatment was carried out in a manner similar to the Example 1-1(1) using Compound 1 (100 mg) and Compound 2 (64 mg) to obtain Compound3 (96 mg).

MS (m/z): 436 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 3 (128 mg) to obtain Compound 4 (102 mg).

MS (m/z): 422 [M+H]⁺

Example 24-2

A treatment was carried out in a manner similar to the Example 24-1 toobtain a compound of Example 24-2 in Table 12 below.

TABLE 12 Example Intermediate 1 Intermediate 2 24-2

MS Example Product (m/z) 24-2

438 [M + H]⁺

Example 25

(1) A treatment was carried out in a manner similar to the Example 11(1) using Compound 1 (1.0 g) to obtain Compound 2 (2.68 g).

MS (m/z): 382/384 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 7 (1)and the Example 1-1 (2) using Compound 2 (1.28 g) and Compound 3 (2.24g) to obtain Compound 4 (1.51 g).

MS (m/z): 496 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 11(3) using Compound 4 (600 mg) and Compound 5 (351 mg) to obtain Compound6 (531 mg).

MS (m/z): 623 [M+H]⁺

(4) A treatment was carried out in a manner similar to the Example 11(4) using Compound 6 (530 mg) to obtain Compound 7 (161 mg).

MS (m/z): 533 [M+H]⁺

(5) Compound 7 (140 mg) was dissolved in acetic acid (2 mL) and water(400 μL), and the mixture was stirred at room temperature for 6 hours.Water, ethyl acetate and tetrahydrofuran were added to the reactionsolution to carry out a liquid separation. The organic layer wasseparated, washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. After theobtained residue was purified by thin-layer silica gel chromatography(chloroform:methanol=5:1), the residue were solidified with addition oft-butyl alcohol and n-hexane, and subsequently the solid was collectedby filtration to obtain Compound 8 (38 mg).

MS (m/z): 493 [M+H]⁺

Example 26-1

A treatment was carried out in a manner similar to the Example 11 (3)using Compound 1 (300 mg) and Compound 2 (99 mg) to obtain Compound 3(161 mg).

MS (m/z): 477 [M+H]⁺

Example 26-2

A treatment was carried out in a manner similar to the Example 26-1 toobtain a compound of Example 26-2 in Table 13 below.

TABLE 13 MS Example Starting material 1 Product (m/z) 26-2

463 [M + H]⁺

Example 27

Compound 1 (60 mg), triethylamine (176 μL), ammonium chloride (68 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl)(173 mg) and 1-hydroxybenzotriazole (HOBt) (51 mg) were added todimethylsulfoxide (1 mL), and the mixture was stirred at roomtemperature overnight. Ethyl acetate and water were added to thereaction solution to carry out a liquid separation. The organic layerwas separated, washed with water, and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by thin layer silica gel columnchromatography (chloroform:methanol=99:1) to obtain Compound 2 (51 mg).

MS (m/z): 475 [M+H]⁺

Example 28

(1) A treatment was carried out in a manner similar to Example 31-1 (3)using Compound 1 (300 mg) and ethyl iodide (70 μL) to obtain Compound 2(270 mg).

MS (m/z): 546 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example10-(4) using Compound 2 (268 mg) to obtain Compound 3 (180 mg).

MS (m/z): 426 [M+H]⁺

(3) A treatment was carried out in a manner similar to Reference Example7-1 (1) and the Example 7 (2) using Compound 3 (179 mg) to obtainCompound 4 (20 mg).

MS (m/z): 410 [M+H]⁺

(4) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 4 (19 mg) to obtain Compound 5 (10 mg).

MS (m/z): 396 [M+H]⁺

Example 29-1

(1) Compound 1 (see Example 24-2) (50 mg) and N-chlorosuccinimide (16.3mg) were added to N,N-dimethylformamide (0.6 mL), and the mixture wasstirred at room temperature overnight. The separately prepared Compound1 (250 mg) and N-chlorosuccinimide (81.3 mg) were added toN,N-dimethylformamide (3.1 mL), and the mixture was stirred at roomtemperature overnight. The above reaction solutions are combined, andethyl acetate and an aqueous saturated sodium hydrogen carbonatesolution were added to carry out a liquid separation. The organic layerwas separated and washed with saturated brine and water, andsubsequently the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=80:20 to 67:33) to obtain Compound 2 (236 mg).

MS (m/z): 486/488 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 2 (235 mg) to obtain Compound 3 (237 mg).

MS (m/z): 472/474 [M+H]⁺

Examples 29-2 to 29-3

A treatment was carried out in a manner similar to the Example 29-1 toobtain compounds of Examples 29-2 and 29-3 in Table 14 below.

TABLE 14 Example Intermediate 29-2

29-3

MS Example Product (m/z) 29-2

397/399 [M + H]⁺ 29-3

406/408/410 [M + H]⁺

Example 30

(1) A treatment was carried out in a manner similar to the Example 7 (1)using Compound 1 (2.0 g) and Compound 2 (2.42 g) to obtain Compound 3(2.00 g).

MS (m/z): 516/518 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 7 (2)using Compound 3 (950 mg) to obtain Compound 4 (665 mg).

MS (m/z): 386/388 [M+H]⁺

(3) Compound 4 (50 mg), N,N-dimethylformamide diethyl acetal (33 μL) andtriethylamine (1.8 μL) were added to toluene (1 mL), and the mixture wasstirred at 110° C. overnight. After the reaction solution was cooled toroom temperature, 1N hydrochloric acid (1.3 mL) was added, and themixture was stirred for 30 minutes. A 1N aqueous sodium hydroxidesolution (1.3 mL) and ethyl acetate were added to the reaction solutionto carry out a liquid separation. The organic layer was separated andwashed with 0.1N phosphate buffer (pH 7), and subsequently the solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=80:20 to 70:30) to obtain Compound 5 (34 mg).

MS (m/z): 414/416 [M+H]⁺

(4) Compound 5 (34 mg) was mixed with sodium borohydride (31.1 mg) inmethanol (1.4 mL), to this was added tetrahydrofuran (2 mL), and themixture was stirred at 65° C. for 1 minute and then at room temperaturefor 15 minutes. The reaction solution was concentrated under reducedpressure, and ethyl acetate and water were added to the residue to carryout a liquid separation. The organic layer was separated, and thesolvent was distilled off under reduced pressure. To the obtained solidwas added acetonitrile, and the solid was collected by filtration anddried to obtain Compound 6 (30.5 mg).

MS (m/z): 416/418 [M+H]⁺

(5) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 6 (30.5 mg) to obtain Compound 7 (20 mg).

MS (m/z): 402/404 [M+H]⁺

Example 31-1

(1) A treatment was carried out in a manner similar to the Example 6 (2)using Compound 1 (409 mg) to obtain Compound 2 (411 mg).

MS (m/z): 544/546 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 30(4) using Compound 2 (408 mg) to obtain Compound 3 (357 mg).

MS (m/z): 546/548 [M+H]⁺

(3) Compound 3 (177 mg) was dissolved in N,N-dimethylformamide (1.8 mL)and tetrahydrofuran (1.8 mL), 60% sodium hydride (19.4 mg) was addedunder ice cooling, and the mixture was stirred for 5 minutes. Methyliodide (40 μL) was added, and the mixture was stirred under ice coolingfor 10 minutes and then at room temperature for 2 hours. Water, asaturated aqueous sodium hydrogen carbonate solution and ethyl acetatewere added to the reaction solution to carry out a liquid separation.The organic layer was separated and washed with brine, and subsequentlythe solvent was distilled off under reduced pressure. The obtained solidwas dissolved in methanol (1.8 mL) and tetrahydrofuran (1.8 mL), a 2Naqueous sodium hydroxide solution (1.29 mL) was added, and the mixturewas stirred at room temperature overnight. After acetic acid was addedto the reaction solution, then brine and ethyl acetate were added tocarry out a liquid separation. The organic layer was separated andwashed with 0.1N phosphate buffer (pH 7), and subsequently the solventwas distilled off under reduced pressure to obtain Compound 4 (199 mg).

MS (m/z): 546/548 [M+H]⁺

(4) A treatment was carried out in a manner similar to the Example 7 (2)using Compound 4 (199 mg) to obtain Compound 5 (63 mg).

MS (m/z): 416/418 [M+H]⁺

Example 31-2

A treatment was carried out in a manner similar to the Example 31-1 toobtain a compound of Example 31-2 in Table 15 below.

TABLE 15 Alkylating Example Intermediate agent 31-2

Et—I MS Example Product (m/z) 31-2

430/432 [M + H]⁺

Example 32-1

Compound 1 (see PCT/JP2011/079958) (470 mg) was dissolved in 28% aqueousammonia (20 mL), and the mixture was stirred at room temperature for 4days and at 40° C. overnight. After the reaction solution wasconcentrated under reduced pressure, the obtained residue was purifiedby silica gel column chromatography (chloroform:methanol=100:0 to85:15), subsequently to the obtained solid were added isopropyl alcoholand diisopropyl ether, and the solid was collected by filtration toobtain Compound 2 (300 mg).

MS (m/z): 363 [M+H]⁺

Examples 32-2 to 32-4

A treatment was carried out in a manner similar to the Example 32-1 toobtain compounds of Examples 32-2 to 32-4 in Table 16 below.

TABLE 16 Example Intermediate 32-2

32-3

32-4

MS Example Product (m/z) 32-2

377 [M + H]⁺ 32-3

378 [M + H]⁺ 32-4

364 [M + H]⁺

Example 33

(1) A treatment was carried out in a manner similar to the Example 11(3) using Compound 1 (570 mg) and a 2M dimethyl amine-tetrahydrofuransolution (3.2 mL) to obtain Compound 2 (139 mg).

MS (m/z): 295/297 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 6 (2)using Compound 2 (260 mg) to obtain Compound 3 (292 mg).

MS (m/z): 425/427 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 7 (1)using Compound 3 (292 mg) and Compound 4 (344 mg) to obtain Compound 5(350 mg).

MS (m/z): 577 [M+H]⁺

(4) A treatment was carried out in a manner similar to the Example 6 (7)using Compound 5 (350 mg) to obtain Compound 6 (178 mg).

MS (m/z): 433 [M+H]⁺

Example 34

(1) A treatment was carried out in a manner similar to the Example 7 (1)using Compound 1 (see Reference Example 15-1) (1.5 g) and Compound 2(1.4 g) to obtain Compound 3 (1.35 g).

MS (m/z): 592 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 18-1(2) using Compound 3 (1.30 g) to obtain Compound 4 (860 mg).

MS (m/z): 412 [M+H]⁺

(3) Compound 4 (480 mg), N,N-diisopropylethylamine (408 μL) and ethyliodide (187 μL) were added to N,N-dimethylacetamide (5 mL), and themixture was stirred at room temperature for 4 hours. To the reactionmixture was added water, the supernatant was discarded, the obtainedoily deposit was washed with water and n-hexane, and subsequently ethylacetate and a 10% aqueous citric acid solution were added to carry out aliquid separation. The organic layer was separated, washed with waterand saturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:chloroform=0:100 to40:60) to obtain Compound 5 (359 mg).

MS (m/z): 440 [M+H]⁺

(4) A treatment was carried out in a manner similar to Reference Example7-1 (1) and the Example 7 (2) using Compound 5 (359 mg) and Compound 6(340 mg) to obtain Compound 7 (228 mg).

MS (m/z): 500 [M+H]⁺

(5) A treatment was carried out in a manner similar to the Example 18-1(2) using Compound 7 (225 mg) to obtain Compound 8 (165 mg).

MS (m/z): 410 [M+H]⁺

Example 35-1

(1) Compound 1 (80 mg), Compound 2 (26 mg), 1-hydroxybenzotriazole (25mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36mg) were added to N,N-dimethylformamide (1 mL), and the mixture wasstirred at room temperature overnight. The solvent was distilled offunder reduced pressure, and the obtained residue was purified by thinlayer silica gel chromatography (chloroform:methanol) to obtain Compound3 (40 mg).

MS (m/z): 450/452 [M+H]⁺

(2) Compound 3 (40 mg) was dissolved in a mixed solvent of ethanol anddichloromethane, and a 4N hydrochloric acid-1,4-dioxane solution (23 μL)was added. The reaction solution was concentrated under reducedpressure, and to the obtained solid residue was added diethyl ether, andthe mixture was triturated, filtered and dried to obtain Compound 4(42.8 mg) as a hydrochloride salt.

MS (m/z): 450/452 [M+H]⁺

Example 35-2

A treatment was carried out in a manner similar to the Example 35-1 toobtain a compound of Example 35-2 in Table 17 below.

TABLE 17 Example Intermediate 1 Intermediate 2 35-2

MS Example Product (m/z) 35-2

431 [M + H]⁺

Example 36

(1) Compound 1 (414 mg), Compound 2 (500 mg), copper (I) iodide (16 mg),N,N′-dimethylethylenediamine (19 μL) and potassium phosphate (868 mg)were added to toluene (2.3 mL), and the mixture was stirred at 80° C.overnight. The reaction solution was cooled and subsequently filteredthrough Celite, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=67:33 to 38:62) to obtainCompound 3 (385 mg).

MS (m/z): 363 [M+H]⁺

(2) A treatment was carried out in a manner similar to Example 37-1 (3)using Compound 3 (385 mg) to obtain Compound 4 (268 mg).

MS (m/z): 263 [M+H]⁺

(3) A treatment was carried out in a manner similar to Example 39 (1)using Compound 4 (268 mg) and Compound 5 (400 mg) to obtain Compound 6(80 mg).

MS (m/z): 604 [M+H]⁺

(4) A treatment was carried out in a manner similar to Example 6 (7)using Compound 6 (79 mg) to obtain Compound 7 (28 mg).

MS (m/z): 446 [M+H]⁺

Example 37-1

(1) Compound 1 (18.5 g), Compound 2 (20 g) and potassium carbonate(16.35 g) were added to dimethylsulfoxide (280 mL), and the mixture wasstirred at 90° C. overnight. After the reaction solution was cooled,water and ethyl acetate were added to carry out a liquid separation. Theorganic layer was separated, washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure. To the obtained residue were added n-hexane and ethyl acetate,and the mixture was stirred, and subsequently, the solid was collectedby filtration to obtain Compound 3 (23.21 g).

MS (m/z): 292 [M+H]⁺

(2) Compound 4 (7.44 g) and sodium acetate (4.48 g) were mixed in water(15.2 mL), and the mixture was stirred at 95° C. for 30 minutes and thencooled. Compound 3 (4 g) was dissolved in 28% aqueous ammonia andmethanol (200 mL), and the above-prepared reaction solution was added,and the mixture was stirred at room temperature overnight. The reactionsolution was concentrated under reduced pressure, and ethyl acetate andwater were added to carry out a liquid separation. The organic layer wasseparated, washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.After the obtained residue was purified by NH-silica gel columnchromatography (chloroform:methanol=20:1), the obtained solid was washedwith diisopropyl ether, filtered and dried to obtain Compound 5 (4.14g).

MS (m/z): 398 [M+H]⁺

(3) To Compound 5 (4.14 g) was added trifluoroacetic acid (21 mL), andthe mixture was stirred at room temperature for 30 minutes. To thereaction solution was added diethyl ether (150 mL), and the mixture wasstirred for 10 minutes. The deposited solid was collected by filtration,washed with diethyl ether and dried to obtain Compound 6 (6.33 g).

MS (m/z): 298 [M+H]⁺

(4) Compound 6 (1.50 g) and triethylamine (1.47 mL) were mixed intetrahydrofuran (15 mL), benzyl chloroformate (0.63 mL) was added underice cooling, and the mixture was stirred at room temperature overnight.Water and ethyl acetate were added to the reaction solution to carry outa liquid separation. The organic layer was separated, washed with asaturated aqueous sodium hydrogen carbonate solution and water, anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. To the obtained solid residue was added methanol, andthe solid was collected by filtration to obtain Compound 7 (709 mg).

MS (m/z): 432 [M+H]⁺

(5) A treatment was carried out in a manner similar to Example 6 (2)using Compound 7 (889 mg) to obtain Compound 8 (1.117 g).

MS (m/z): 562 [M+H]⁺

(6) A treatment was carried out in a manner similar to Example 18-1 (2)using Compound 8 (1.11 g) to obtain Compound 9 (833 mg).

MS (m/z): 428 [M+H]⁺

(7) Under a nitrogen atmosphere, palladium acetate (2.7 mg),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-PHOS)(17.3 mg) and water (1.1 μL) were added to 1,4-dioxane (1.7 mL), and themixture was stirred at 80° C. for 2 minutes. Separately, Compound 9 (170mg), Compound 10 (153 mg) and cesium carbonate (197 mg) were mixed undera nitrogen atmosphere, the above prepared solution was added at 80° C.,and subsequently the mixture was stirred at 100° C. overnight. Thereaction solution was filtered through Celite, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=95:5 to70:30) to obtain Compound 11 (163 mg).

MS (m/z): 618 [M+H]⁺

(8) A treatment was carried out in a manner similar to the Example 19-1(2) using Compound 11 (163 mg) to obtain Compound 12 (73 mg).

MS (m/z): 432 [M+H]⁺

Examples 37-2 to 37-6

A treatment was carried out in a manner similar to the Example 37-1 toobtain compounds of Examples 37-2 to 37-6 in Table 18 below.

TABLE 18 Example Intermediate 1 Intermediate 2 37-2

37-3

37-4

37-5

37-6

MS Example Product (m/z) 37-2

446 [M + H]⁺ 37-3

446 [M + H]⁺ 37-4

446 [M + H]⁺ 37-5

450 [M + H]⁺ 37-6

464 [M + H]⁺

Example 38-1

(1) A treatment was carried out in a manner similar to the Example 37-1(1) using Compound 1 (1.0 g) and Compound 2 (818 mg) to obtain Compound3 (1.457 g).

MS (m/z): 289 [M+H]⁺

(2) A treatment was carried out in a manner similar to Reference Example7-1 (4) using Compound 3 (4.0 g) to obtain Compound 4 (4.23 g).

MS (m/z): 322 [M+H]⁺

(3) A treatment was carried out in a manner similar to Reference Example7-1 (5) using Compound 4 (2.23 g) to obtain Compound 5 (2.51 g).

MS (m/z): 306 [M+H]⁺

(4) A treatment was carried out in a manner similar to the Example 1-1(1) using Compound 5 (2.94 g) and Compound 6 (1.99 g) to obtain Compound7 (345 mg).

MS (m/z): 372 [M+H]⁺

(5) A treatment was carried out in a manner similar to the Example 6 (2)using Compound 7 (337 mg) to obtain Compound 8 (422 mg).

MS (m/z): 502 [M+H]⁺

(6) To Compound 8 (416 mg) was added a 4N hydrochloric acid-1,4-dioxanesolution (4 mL), and the mixture was stirred at room temperature for 30minutes. To the reaction solution was added diethyl ether, and thedeposited solid was collected by filtration, washed with diethyl etherand then dried to obtain Compound 9 (345 mg).

MS (m/z): 402 [M+H]⁺

(7) Compound 9 (338 mg), Compound 10 (290 mg),tris(dibenzylideneacetone)dipalladium(0) (33 mg),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-PHOS) (33mg) and cesium carbonate (928 mg) were added to toluene (4 mL) under anitrogen atmosphere, and the mixture was stirred at 80° C. overnight.The reaction solution was filtered using NH-silica gel, and the filtratewas purified by silica gel column chromatography (n-hexane:ethylacetate=75:25 to 50:50) to obtain Compound 11 (156 mg).

MS (m/z): 592 [M+H]⁺

(8) A treatment was carried out in a manner similar to the Example 19-1(2) using Compound 11 (150 mg) to obtain Compound 12 (42 mg).

MS (m/z): 406 [M+H]⁺

Examples 38-2 to 38-5

A treatment was carried out in a manner similar to the Example 38-1 toobtain compounds of Examples 38-2 to 38-5 in Table 19 below.

TABLE 19 Example Intermediate 1 Intermediate 2 Intermediate 3 38-2

38-3

38-4

38-5

Example Product MS (m/z) 38-2

404 [M + H]⁺ 38-3

406 [M + H]⁺ 38-4

406 [M + H]⁺ 38-5

418 [M + H]⁺

Example 39

(1) Compound 1 (330 mg) was dissolved in dimethylsulfoxide (7 mL), andCompound 2 (290 mg) and potassium carbonate (140 mg) were added, and themixture was stirred at 100° C. overnight. Water and ethyl acetate wereadded to the reaction solution to carry out a liquid separation. Theorganic layer was separated, washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=78:22 to 63:37) to obtainCompound 3 (263 mg).

MS (m/z): 590 [M+H]⁺

(2) Lithium aluminum hydride (16 mg) was suspended in tetrahydrofuran (2mL), and a solution of Compound 3 (256 mg) in tetrahydrofuran (3 mL) wasadded dropwise at room temperature. After the mixture was stirred for 1hour, additional lithium aluminum hydride (16 mg) was added portionwise,and the mixture was further stirred for 30 minutes. To the reactionsolution were added sodium sulfate (0.2 g) and water (0.2 g) under icecooling, and the mixture was stirred at room temperature for 30 minutes.The insoluble matter was filtered, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=70:30 to 25:75) to obtainCompound 4 (218 mg).

MS (m/z): 548 [M+H]⁺

(3) A treatment was carried out in a manner similar to Example 7 (2)using Compound 4 (214 mg) to obtain Compound 5 (54 mg).

MS (m/z): 418 [M+H]⁺

Example 40-1

(1) Compound 1 (200 mg), Compound 2 (123 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (178 mg) andN,N-dimethylaminopyridine (DMAP) (6 mg) were added to dimethylacetamide(5 mL), and the mixture was stirred at room temperature for two days.Ethyl acetate and a 10% aqueous citric acid solution were added to thereaction solution to carry out a liquid separation. The organic layerwas separated, washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. After the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 30:70), diisopropylether and n-hexane were added, and the solid was collected by filtrationto obtain Compound 3 (191 mg).

MS (m/z): 546 [M+H]⁺

(2) Compound 3 (157 mg) was dissolved in methanol (6 mL) and to this wasadded 1N hydrochloric acid (2 mL), and the mixture was stirred at roomtemperature overnight. The reaction solution was concentrated underreduced pressure, and an aqueous saturated sodium hydrogen carbonatesolution, ethyl acetate and tetrahydrofuran were added to the obtainedresidue under ice cooling to carry out a liquid separation. The organiclayer was separated, washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. After the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 80:20), isopropyl etherand n-hexane were added, and the solid was collected by filtration toobtain Compound 4 (75 mg) and Compound 5 (20 mg).

Compound 4 MS (m/z): 506 [M+H]⁺

Compound 5 MS (m/z): 446 [M+H]⁺

Example 40-2

A treatment was carried out in a manner similar to the Example 40-1 toobtain a compound of Example 40-2 in Table 20 below.

TABLE 20 Example Starting material 1 Starting material 2 40-2

Example Product MS (m/z) 40-2

596 [M + H]⁺

Example 41-1

(1) Compound 1 (200 mg), Compound 2 (122 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (178 mg) and1-hydroxybenzotriazole (125 mg) were added to dimethylformamide (5 mL),and the mixture was stirred at room temperature overnight. Ethylacetate, n-hexane and water were added to the reaction solution to carryout a liquid separation. The organic layer was separated, washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. After the obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=100:0 to 90:10), diisopropyl ether and n-hexane were added, andthe solid was collected by filtration to obtain Compound 3 (241 mg).

MS (m/z): 545 [M+H]⁺

(2) Compound 3 (164 mg) was dissolved in 1,4-dioxane (5 mL) andconcentrated hydrochloric acid (5 mL), and the mixture was stirred atroom temperature for 6 hours. A saturated aqueous sodium hydrogencarbonate solution was added under ice cooling, and ethyl acetate andtetrahydrofuran were further added to carry out a liquid separation. Theorganic layer was separated, washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. To the obtained residue were added diisopropyl ether andisopropyl alcohol, and the solid was collected by filtration to obtainCompound 4 (58 mg).

MS (m/z): 505 [M+H]⁺

Examples 41-2 to 41-3

A treatment was carried out in a manner similar to the Example 41-1 toobtain compounds of Examples 41-2 and 41-3 in Table 21 below.

TABLE 21 Example Starting material 1 Starting material 2 41-2

41-3

Example Product MS (m/z) 41-2

519 [M + H]⁺ 41-3

519 [M + H]⁺

Example 42

(1) To a solution of Compound 1 (200 mg) in toluene (10 mL) were addedsequentially imidazole (153 mg), triphenylphosphine (590 mg) and iodine(457 mg), and the mixture was stirred at room temperature for 30minutes. The reaction solution was diluted with ethyl acetate, to thiswas added an aqueous sodium sulfite solution, and the mixture wasstirred. The organic layer was separated, washed with saturated brine,and dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure.

To a solution of Compound 2 (180 mg) in N,N-dimethylformamide (4 mL) wasadded 60% sodium hydride (43 mg) under ice cooling, and the mixture wasstirred at room temperature for 30 minutes. Then, a solution of theabove residue in N,N-dimethylformamide (2 mL) was added, and the mixturewas stirred at room temperature overnight. To the reaction solution wasadded a saturated aqueous ammonium chloride solution, and then ethylacetate and water were added to carry out a liquid separation. Theorganic layer was separated, washed with water, and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=67:33 to 40:60) to obtain Compound 3 (44 mg).

MS (m/z): 405 [M+H]⁺

(2) Compound 3 (50 mg) was dissolved in 4N hydrochloric acid-1,4-dioxanesolution (1 mL), and the mixture was stirred at room temperatureovernight. The reaction solution was concentrated under reducedpressure, the obtained residue was dissolved in dimethylsulfoxide (1mL), potassium carbonate (51 mg) and 6-bromonicotinaldehyde (30 mg) wereadded, and the mixture was stirred at 100° C. for 3 hours. After thereaction solution was cooled, ethyl acetate and water were added tocarry out a liquid separation. The organic layer was separated, washedwith water, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure.

Compound 4 (100 mg) and sodium acetate (71 mg) were added to water (1mL), and the mixture was stirred at 95° C. for 30 minutes. This wascooled to room temperature, to this were added a solution of the aboveresidue in 25% aqueous ammonia (1 mL) and methanol (3 mL), and themixture was stirred at room temperature overnight. Ethyl acetate andwater to the reaction solution were added to carry out a liquidseparation. The organic layer was separated, washed with water, anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by thin layer silicagel chromatography (chloroform:methanol=9:1) to obtain Compound 5 (30mg).

MS (m/z): 516 [M+H]⁺

(3) A treatment was carried out in a manner similar to Example 18-1 (2)using Compound 5 (30 mg) to obtain Compound 6 (18.9 mg).

MS (m/z): 426 [M+H]⁺

Example 43-1

(1) Compound 1 (589 mg), Compound 2 (390 mg) and potassium carbonate(371 mg) were added to dimethylsulfoxide (8 mL), and the mixture wasstirred at 100° C. overnight. Water and ethyl acetate were added to thereaction solution to carry out a liquid separation. The organic layerwas separated, washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=85:15 to 70:30) to obtain Compound 3 (467 mg).

MS (m/z): 591 [M+H]⁺

(2) A treatment was carried out in a manner similar to Example 1-1 (2)using Compound 3 (467 mg) to obtain Compound 4 (446 mg).

MS (m/z): 577 [M+H]⁺

(3) A treatment was carried out in a manner similar to Example 7 (2)using Compound 4 (440 mg) to obtain Compound 5 (292 mg).

MS (m/z): 447 [M+H]⁺

Examples 43-2 to 43-7

A treatment was carried out in a manner similar to the Example 43-1 toobtain compounds of Examples 43-2 to 43-7 in Table 22 below.

TABLE 22 Example Starting material 1 Starting material 2 43-2

43-3

43-4

43-5

43-6

43-7

Example Product MS (m/z) 43-2

431 [M + H]⁺ 43-3

413 [M + H]⁺ 43-4

431 [M + H]⁺ 43-5

445 [M + H]⁺ 43-6

445 [M + H]⁺ 43-7

411 [M + H]⁺

Example 44-1

(1) A treatment was carried out in a manner similar to the Example 43-1(1) using Compound 1 (1 g) and Compound 2 (0.545 g) to obtain Compound 3(1.95 g).

MS (m/z): 457 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 18-1(3) using Compound 3 (0.246 g) and Compound 4 (0.179 g) to obtainCompound 5 (0.253 g).

MS (m/z): 605 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 5 (0.252 g) to obtain Compound 6 (0.242 g).

MS (m/z): 591 [M+H]⁺

(4) A treatment was carried out in a manner similar to the Example 7 (2)using Compound 6 (0.241 g) to obtain Compound 7 (0.164 g).

MS (m/z): 461 [M+H]⁺

Examples 44-2 to 44-11

A treatment was carried out in a manner similar to the Example 44-1 toobtain compounds of Examples 44-2 to 44-11 in Table 23 below.

TABLE 23 Example Intermediate 1 Intermediate 2 44-2

44-3

44-4

44-5

44-6

44-7

44-8

44-9

 44-10

 44-11

Example Product MS (m/z) 44-2

461 [M + H]⁺ 44-3

461 [M + H]⁺ 44-4

461 [M + H]⁺ 44-5

465 [M + H]⁺ 44-6

481/483 [M + H]⁺ 44-7

447 [M + H]⁺ 44-8

477 [M + H]⁺ 44-9

443 [M + H]⁺  44-10

447 [M + H]⁺  44-11

447 [M + H]⁺

Example 45-1

(1) Compound 1 (395 mg), Compound 2 (500 mg),tris(dibenzylideneacetone)dipalladium(0) (22 mg),4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (Xantphos) (41 mg) andsodium t-butoxide (342 mg) were added to toluene (10 mL), and themixture was stirred under a nitrogen atmosphere at 100° C. for 3 hours.Ethyl acetate and water were added to the reaction solution to carry outa liquid separation. The organic layer was separated, washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=95:5 to 80:20)to obtain Compound 3 (121 mg).

MS (m/z): 618 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 6 (7)using Compound 3 (120 mg) to obtain Compound 4 (34 mg).

MS (m/z): 460 [M+H]⁺

Examples 45-2 to 45-3

A treatment was carried out in a manner similar to the Example 45-1 toobtain compounds of Examples 45-2 and 45-3 in Table 24 below.

TABLE 24 Example Starting material 1 Starting material 2 45-2

45-3

Example Product MS (m/z) 45-2

461 [M + H]⁺ 45-3

432 [M + H]⁺

Example 46-1

(1) Compound 1 (5 g) and 2,6-lutidine (5.13 mL) were dissolved inmethylene chloride (50 mL), trifluoromethanesulfonic anhydride (9.88 mL)was added dropwise under ice cooling over 30 minutes, and the mixturewas stirred at room temperature for 1 hour. Additionaltrifluoromethanesulfonic anhydride (2.4 mL) was added dropwise, and themixture was stirred at room temperature for 3 hours. After the reactionsolution was concentrated under reduced pressure, the obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=90:10) to obtain Compound 2 (5.44 g).

MS (m/z): 303 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 9 (2)using Compound 2 (5.4 g) to obtain Compound 3 (4.42 g).

MS (m/z): 281 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 7 (1)using Compound 3 (4.4 g) and Compound 4 (6.15 g) to obtain Compound 5(6.06 g).

MS (m/z): 496 [M+H]⁺

(4) Compound 5 (5.73 g) and 10% palladium-carbon (0.57 g) were mixed inethanol (115 mL), and the mixture was stirred under a hydrogenatmosphere at room temperature for 6 hours. The reaction solution wasfiltered, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 66:34) to obtain Compound 6 (5.35 g).

MS (m/z): 498 [M+H]⁺

(5) A treatment was carried out in a manner similar to the Example 10(2) using Compound 6 (0.906 g) to obtain Compound 7 (446 mg) andCompound 8 (176 mg).

MS (m/z): 456 [M+H]⁺

(6) Compound 8 (165 mg) was dissolved in methylene chloride (3.3 mL),then diisopropyl ethyl amine (126 μL) and methanesulfonyl chloride (42μL) were added under ice cooling, and the mixture was stirred at roomtemperature for 50 minutes. Diethyl ether and water were added to thereaction solution to carry out a liquid separation. The organic layerwas separated, washed with water, and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure. Compound9 (83 mg) was dissolved in N,N-dimethylformamide (1.6 mL), 60% sodiumhydride (24.6 mg) was added under ice cooling, and the mixture wasstirred at room temperature for 30 minutes. To this was added a solutionof the above residue in N,N-dimethylformamide (1.6 mL), and the mixturewas stirred at 70° C. for 3 hours. After the reaction solution wascooled, water and ethyl acetate were added to carry out a liquidseparation. The organic layer was separated, washed with water andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=95:5 to 80:20) to obtain Compound 10 (107 mg).

MS (m/z): 590 [M+H]⁺

(7) A treatment was carried out in a manner similar to Example 1-1 (2)and Example 7 (2) using Compound 10 (97 mg) to obtain Compound 11 (79mg).

MS (m/z): 446 [M+H]⁺

Examples 46-2 to 46-7

A treatment was carried out in a manner similar to the Example 46-1 toobtain compounds of Examples 46-2 to 46-7 in Table 25 below.

TABLE 25 Example Intermediate 1 Intermediate 2 46-2

46-3

46-4

46-5

46-6

46-7

Example Product MS (m/z) 46-2

446 [M + H]⁺ 46-3

460 [M + H]⁺ 46-4

460 [M + H]⁺ 46-5

464 [M + H]⁺ 46-6

480/482 [M + H]⁺ 46-7

444 [M + H]⁺

Example 47-1

(1) A treatment was carried out in a manner similar to the Example 18-1(3) using Compound 1 (91 mg) and Compound 2 (61 mg) to obtain Compound 3(70 mg).

MS (m/z): 591 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 1-1(2) and Example 7 (2) using Compound 3 (67 mg) to obtain Compound 4 (41mg).

MS (m/z): 447 [M+H]⁺

Example 47-2

A treatment was carried out in a manner similar to the Example 47-1 toobtain a compound of Example 47-2 in Table 26 below.

TABLE 26 Example Intermediate 1 Intermediate 2 47-2

Example Product MS (m/z) 47-2

447 [M + H]⁺

Example 48

(1) Compound 1 (see US2010/267689) (320 mg) and2,6-di-t-butyl-4-methylpyridine (197 μL) were dissolved in methylenechloride (8 mL), trifluoromethanesulfonic anhydride (238 μL) was added,and the mixture was stirred at room temperature overnight. Water wasadded to the reaction solution to carry out a liquid separation. Theorganic layer was separated, and the solvent was distilled off underreduced pressure. To the obtained residue was added diisopropyl ether tobe mixed. The insoluble substance was filtered out. The filtrate wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=95:5 to 85:15) to obtain Compound 2 (181 mg).

MS (m/z): 393 [M+H]⁺

(2) A treatment was carried out in a manner similar to the Example 9 (2)using Compound 2 (180 mg) to obtain Compound 3 (202 mg).

MS (m/z): 388 [M+NH4]⁺

(3) A treatment was carried out in a manner similar to the Example 7 (1)using Compound 3 (210 mg) and Compound 4 (150 mg) to obtain Compound 5(56 mg).

MS (m/z): 586 [M+H]⁺

(4) Compound 5 (56 mg) was dissolved in ethanol (2.2 mL) and ethylacetate (0.56 mL), 10% palladium-carbon (11 mg) was added, and themixture was stirred under a hydrogen atmosphere at room temperature for6 hours. The reaction solution was filtered through a membrane-filter,and the filtrate was concentrated under reduced pressure to obtainCompound 6 (55 mg).

MS (m/z): 588 [M+H]⁺

(5) A treatment was carried out in a manner similar to Example 1-1 (2)and Example 7 (2) using Compound 6 (54 mg) to obtain Compound 7 (28 mg).

MS (m/z): 430 [M+H]⁺

Example 49

(1) Compound 1 (4.5 g) was dissolved in N,N-dimethylformamide (45 mL),to this was added sodium hydride (1.37 g) under ice cooling, and themixture was stirred under a nitrogen stream for 30 minutes. To this wasadded dropwise Compound 2 (5.09 g), and the mixture was stirred at 0° C.for 30 minutes and then at room temperature for 1 hour. Water and ethylacetate were added to the reaction solution to carry out a liquidseparation. The organic layer was separated, washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=95:5 to65:35) to obtain Compound 3 (3.13 g).

MS (m/z): 257 [M+H]⁺

(2) 60% Sodium hydride (537 mg) was suspended in dimethylsulfoxide (4mL), and trimethylsulfonium iodide (2.95 g) was added, and the mixturewas stirred at room temperature for 1 hour. To this was added dropwise asolution of Compound 3 (3.13 g) in dimethylsulfoxide (2 mL), and themixture was stirred at room temperature for 3 days. Water and diethylether were added to the reaction solution to carry out a liquidseparation. The organic layer was separated and washed with saturatedbrine, and then the solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 65:35) to obtain Compound 4 (898 mg).

MS (m/z): 271 [M+H]⁺

(3) Compound 4 (100 mg) was dissolved in acetic acid (2 mL), andplatinum oxide (10 mg) was added under a nitrogen atmosphere, and themixture was stirred under a hydrogen atmosphere at room temperature for8 hours. The reaction solution was filtered through a membrane-filter,and the filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=90:10 to 35:65) to obtain Compound 5 (41 mg).

MS (m/z): 273 [M+H]⁺

(4) Compound 5 (355 mg) was dissolved in trifluoroacetic acid (0.3 mL),water (1 mL) and tetrahydrofuran (3 mL), and the mixture was stirred at65° C. for 3 hours. Water, an aqueous sodium hydrogen carbonate solutionand ethyl acetate were added to the reaction solution to carry out aliquid separation. The organic layer was separated and washed withsaturated brine, and then the solvent was distilled off under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=90:10 to 65:35) to obtainCompound 6 (242 mg).

MS (m/z): 229 [M+H]⁺

(5) Compound 6 (230 mg) and N-phenylbis(trifluoromethanesulfonamide)(719 mg) were dissolved in tetrahydrofuran (5 mL), 0.5N potassiumhexamethyldisilazane (4.03 mL) was added dropwise under a nitrogenatmosphere at −78° C., and the mixture was stirred for 1 hour. Water, anaqueous saturated ammonium chloride solution and ethyl acetate wereadded to the reaction solution to carry out a liquid separation. Theorganic layer was separated and washed with saturated brine, andsubsequently the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=96:4 to 80:20) and NH-silica gel columnchromatography (n-hexane:ethyl acetate=98:2 to 92:8) to obtain Compound7 (623 mg).

MS (m/z): 361 [M+H]⁺

(6) A treatment was carried out in a manner similar to the Example 9 (2)using Compound 7 to obtain Compound 8.

MS (m/z): 339 [M+H]⁺

(7) A treatment was carried out in a manner similar to the Example 7 (1)using Compound 8 to obtain Compound 10.

MS (m/z): 554 [M+H]⁺

(8) Compound 10 (257 mg) was suspended in methanol (4 mL) andtetrahydrofuran (2 mL), 10% palladium-carbon (26 mg) was added under anitrogen atmosphere, and the mixture was stirred under a hydrogenatmosphere at room temperature for 5 hours. The reaction solution wasfiltered through a membrane-filter, and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=80:20 to 60:40) to obtainCompound 11 (220 mg).

MS (m/z): 556 [M+H]⁺

(9) A treatment was carried out in a manner similar to the Example 1-1(2) using Compound 11 (218 mg) to obtain Compound 12 (131 mg).

MS (m/z): 542 [M+H]⁺

(10) A treatment was carried out in a manner similar to the Example 7(2) using Compound 12 (130 mg) to obtain Compound 13 (4.8 mg).

MS (m/z): 412 [M+H]⁺

Example 50

(1)

To ethanol (250 mL) was added Compound 1 (10 g), and the mixture wasice-cooled. Hydrochloric acid gas was blown for 10 minutes. The reactionsolution was stirred at room temperature overnight and subsequentlyconcentrated under reduced pressure to obtain Compound 2 (12.53 g) as awhite powder.

MS (m/z): 228/230 [M+H]⁺

(2)

Compound 2 (12.53 g) was dissolved in ethanol (94 mL), and a 7Nammonia/methanol solution (31.5 mL) was added dropwise at roomtemperature over 5 minutes. After the reaction solution was stirred atroom temperature for 3 hours, an additional 7N ammonia/methanol solution(15.7 mL) was added, and the mixture was stirred overnight. The reactionsolution was concentrated under reduced pressure, to the obtained whitesolid was added diethyl ether, and the mixture was stirred.Subsequently, the solid was collected by filtration and dried to obtainCompound 3 (13.25 g) as a white powder.

MS (m/z): 199/201 [M+H]⁺

(3)

Compound 3 (13.25 g) was suspended in water (40 mL), and a 5N aqueoussodium hydroxide solution (40 mL) was added, and the mixture was stirredat room temperature for 3 hours. The deposit was collected by filtrationand washed with water. The obtained white solid was dissolved inacetone, activated charcoal was added, and the mixture was stirred for10 minutes, and subsequently, filtered through Celite. The filtrate wasconcentrated under reduced pressure, and the obtained powder was washedwith diethyl ether, collected by filtration and dried to obtain Compound4 (9.58 g) as a white powder.

(4)

To tetrahydrofuran (6 mL) were added ethyl trifluoroacetate (598 μL) andhydrazine hydrate (232 μL), and the mixture was stirred at 65° C. for 1hour. To the reaction solution was added Compound 4 (1 g), and themixture was stirred at 65° C. for 4.5 hours. Water was added, and themixture was extracted with ethyl acetate, washed with saturated brine,and dried over anhydrous magnesium sulfate. After the mixture was driedand concentrated under reduced pressure, the obtained solid wasdissolved in ethyl acetate, activated charcoal was added, and themixture was stirred. Subsequently, the mixture was filtered out throughCelite. The filtrate was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 80:20) to obtain Compound 5 (1.082 g)as a white solid.

MS (m/z): 292/294 [M+H]⁺

(5)

Compound 5 (1 g) was dissolved in N,N-dimethylformamide (25 mL), sodiumhydride (212 mg) was added under ice cooling, and the mixture wasstirred for 40 minutes. At the same temperature,2-(chloromethoxy)ethyltrimethylsilane (910 μL) was added, thetemperature was elevated to room temperature, and the mixture wasstirred for 5 hours. An aqueous saturated sodium hydrogen carbonatesolution was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=90:10 to 80:20) to obtain a mixture of Compounds 6a and 6b(10:9) as a colorless liquid.

MS (m/z): 422/424 [M+H]⁺

(6)

The mixed solution of the mixture of Compounds 6a and 6b (202 mg),Compound 7 (242 mg), a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (20 mg), N,N-dimethylformamide (5 mL) and a 2Naqueous sodium carbonate solution (950 μL) was stirred at 80° C. for 19hours. The reaction solution was filtered through Celite, and to thefiltrate was added water, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and concentrated.The obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 85:15) to obtain a mixture of Compounds8a and 8b (278 mg) as a pale yellow solid.

MS (m/z): 574 [M+H]⁺

(7)

To the mixture of Compounds 8a and 8b (272 mg) were addedtrifluoroacetic acid (5.4 mL) and water (540 μL), and the mixture wasstirred at room temperature for 7 hours. The reaction solution wasconcentrated under reduced pressure, and to the obtained solid was addedcold methanol, and the mixture was sonicated. The obtained suspensionwas filtered and then washed with cold methanol to obtain Compound 9(152 mg) as a white solid.

MS (m/z): 444 [M+H]⁺

(8)

To Compound 9 (150 mg) were added tetrahydrofuran (6 mL), methanol (6mL), and an 8N aqueous sodium hydroxide solution (0.175 mL), and themixture was stirred at room temperature overnight. To the reactionsolution were added acetic acid (2 mL) and water (2 mL), and thesolution was concentrated under reduced pressure. The obtained solid wassuspended in cold methanol, collected by filtration and washed withwater and methanol. The obtained white powder was purified using LC-MS,the obtained fraction was concentrated, and water (3 mL) and methanol(0.5 mL) were added. Then, the mixture was suspended by sonification,acetic acid (200 μL) was added, and the mixture was stirred. Theobtained powder was collected by filtration, washed with water andmethanol and dried to obtain Compound 10 (27 mg).

MS (m/z): 430 [M+H]⁺

Example 51

(1)

Sodium hydride (15.6 g) was suspended in 300 mL of tetrahydrofuran undera nitrogen stream, and Compound 1 (30 mL) was added dropwise over 30minutes under ice cooling. After the mixture was stirred under icecooling for 30 minutes, methyl iodide (24.3 mL) was added dropwise, andthe mixture was stirred at room temperature for 16 hours. To thereaction solution was added water, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solution was concentrated underreduced pressure to obtain Compound 2 (24.76 g). The obtained Compound 2(24.76 g) was dissolved in tetrahydrofuran (320 mL), 1M lithiumhydroxide tri-tert-butoxyaluminum (300 mL) was added dropwise over 45minutes under a nitrogen stream at room temperature, and the mixture washeated at reflux for 2 hours. To the reaction solution was addedsaturated brine, and the mixture was filtered through Celite and washedwith ethyl acetate. The filtrate was concentrated under reducedpressure, to the concentrated residue were added ethyl acetate andwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.After the solution was concentrated under reduced pressure, the obtainedresidue was distilled under reduced pressure to obtain Compound 3 (13.52g).

MS (m/z): 175 [M+H]⁺

(2)

Compound 3 (1005 mg), Compound 4 (500 mg) and triphenylphosphine (1500mg) were dissolved in tetrahydrofuran (8 mL), a 40% solution of diethylazodicarboxylate in toluene (2.65 mL) was added, and the mixture wasstirred at 80° C. for 3 hours. To the reaction solution was added water,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. After thesolution was concentrated under reduced pressure, the obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=93:7 to 90:10) to obtain Compound 5 (810 mg) as a pink liquid.

MS (m/z): 330/332 [M+H]⁺

(3)

To a mixture of Compounds 6a and 6b (1000 mg), potassium acetate (700mg) and bis(pinacolato)diboron (755 mg) was added 1,4-dioxane (24 mL),and the mixture was subjected to nitrogen substitution. Then, a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (58 mg) and (diphenylphosphino)ferrocene (40 mg)were added, and the mixture was subjected to nitrogen substitution againand stirred at 80° C. for 21 hours. To the reaction solution were addedwater and ethyl acetate, and the mixture was stirred and subsequentlyfiltered through Celite. The filtrate was extracted with ethyl acetate,washed with saturated brine and dried. After the solution wasconcentrated under reduced pressure, the obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=95:5 to85:15) to obtain a mixture of Compounds 7a and 7b (986 mg) as a whitesolid.

MS (m/z): 470 [M+H]⁺

(4)

A mixture of the mixture of Compounds 7a and 7b (150 mg), Compound 5(135 mg), N,N-dimethylformamide (3 mL) and a 2M aqueous sodium carbonatesolution (0.64 mL) was subjected to nitrogen substitution, then a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (29 mg) was subsequently added, and the mixturewas stirred at 80° C. for 15 hours. To the reaction solution was addedwater, and the mixture was extracted with ethyl acetate, washed withsaturated brine and dried over anhydrous sodium sulfate. After thesolution was concentrated under reduced pressure, the obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=95:5 to 90:10) to obtain a mixture of Compounds 8a and 8b (125mg) as a pale yellow viscous material.

MS (m/z): 593 [M+H]⁺

(5)

To the mixture of Compounds 8a and 8b (125 mg) were addedtrifluoroacetic acid (2.5 mL) and water (0.25 mL), and the mixture wasstirred at room temperature for 16 hours. The reaction solution wasconcentrated under reduced pressure, the residue was dissolved intetrahydrofuran, the solution was neutralized with 1N sodium hydroxide,and 0.1M phosphate buffer having pH 7 (2 mL) was added. This was washedwith ethyl acetate, and the aqueous layer was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=80:20 to 60:40) to obtainCompound 9 (26 mg) as a white solid.

MS (m/z): 407 [M+H]⁺

Example 52

(1)

A reaction was carried out in a manner similar to the Example 50-(1)using Compound 1 (5 g) to obtain Compound 2 (7.98 g) as a pale yellowpowder.

MS (m/z): 185/187 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 50-(2)using Compound 2 (7.98 g) to obtain Compound 3 (6.29 g) as a red powder.

MS (m/z): 156/158 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 50-(3)using Compound 3 (6.29 g) to obtain Compound 4 (2.49 g) as a pinkpowder.

MS (m/z): 156/158 [M+H]⁺

(4)

A reaction was carried out in a manner similar to the Example 50-(4)using Compound 4 (2.48 g) to obtain Compound 5 (2.91 g) as a pinkpowder.

MS (m/z): 249 [M+H]⁺

(5)

A reaction was carried out in a manner similar to the Example 50-(5)using Compound 5 (2.91 g) to obtain Compound 6a (2.18 g) as a colorlesssolid and Compound 6b (2.09 g) as a colorless oil.

MS (m/z): 379/381 [M+H]⁺

(6)

A reaction was carried out in a manner similar to the Example 50-(6)using Compound 6a (500 mg) and Compound 7 (881 mg) to obtain Compound 8(563 mg) as a colorless powder.

MS (m/z): 575 [M+H]⁺

(7)

A mixture of Compound 8 (563 mg), methanol (5.6 mL), tetrahydrofuran(9.6 mL) and a 2N aqueous sodium hydroxide solution (3.92 mL) wasstirred at room temperature for 14 hours. After the mixture wasneutralized by addition of acetic acid, the mixture was concentratedunder reduced pressure, to the obtained residue was added water, themixture was extracted with ethyl acetate. The extract was washed with0.1N phosphate buffer having pH 7, filtered and concentrated underreduced pressure. The obtained solid was recrystallized from methanol toobtain Compound 9 (353 mg) as a colorless powder. Further, theconcentrated residue of the mother liquid was purified by silica gelcolumn chromatography (chloroform:methanol=100:0 to 96:4) to obtainCompound 9 (67 mg) as a white solid.

MS (m/z): 561 [M+H]⁺

(8)

Compound 9 (419 mg) was dissolved in trifluoroacetic acid (8.38 mL) andwater (0.84 mL), and the mixture was stirred at room temperature for 16hours. The reaction solution was concentrated under reduced pressure,and the obtained deposit was washed with acetonitrile, andrecrystallized from acetonitrile. The crystals were collected byfiltration and dried under reduced pressure at 50° C. to obtain Compound10 (223 mg) as a white solid.

MS (m/z): 431 [M+H]⁺

Example 53

(1)

A mixed solution of Compound 1 (1000 mg), Compound 2 (1085 mg), a 2Maqueous sodium carbonate solution (4736 μL) and N,N-dimethylformamide(20 mL) was subject to nitrogen substitution, and subsequently a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (193 mg) was added, and the mixture was stirredat 80° C. overnight. To the reaction solution were added water and ethylacetate, and the mixture was stirred at room temperature for 30 minutes,and filtered through Celite. The filtrate was extracted with ethylacetate, and the extract was washed with water, and dried over anhydroussodium sulfate. The solution was concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=95:5 to 80:20) to obtain Compound3 (1288 mg) as a colorless solid.

MS (m/z): 527 [M+H]⁺

(2)

Compound 3 (1285 mg) was dissolved in ethanol (26 mL), and the mixturewas subjected to nitrogen substitution. Subsequently, palladium carbon(386 mg) was added, and the mixture was stirred under a hydrogenatmosphere at room temperature for 6 hours. The reaction solution wasfiltered through Celite and washed with tetrahydrofuran. After thefiltrate was concentrated under reduced pressure, the obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=80:20 to 60:40) to obtain Compound 4 (966 mg) as a colorlesssolid.

MS (m/z): 437 [M+H]⁺

(3)

Compound 5 (20.04 g) and imidazole (15.84 g) were dissolved inN,N-dimethylformamide (116 mL), tert-butyldimethylsilyl chloride (19.47g) was added under ice cooling, and the mixture was stirred at roomtemperature for 15 hours. The reaction solution was added to ice water,and the mixture was extracted with diethyl ether. The extract was washedwith water and saturated brine. The solution was dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to obtainCompound 6 (34.94 g) as a colorless oil.

MS (m/z): 287 [M+H]⁺

(4)

Compound 6 (34.93 g) was dissolved in tetrahydrofuran (241 mL), a 2Naqueous sodium hydroxide solution (244 mL) was added, and the mixturewas stirred at 70° C. for 15 hours. Tetrahydrofuran was distilled offunder reduced pressure, and the aqueous solution was washed withn-hexane and diethyl ether. The aqueous layer was adjusted to pH=4 witha 1N aqueous citric acid solution, and the mixture was extracted withdiethyl ether. The extract was dried over anhydrous magnesium sulfateand concentrated under reduced pressure to obtain Compound 7 (26.17 g)as a colorless solid.

MS (m/z): 259 [M+H]⁺

(5)

Compound 7 (33.75 g) and Boc₂O (34.2 g) were dissolved in tert-butanol(338 mL), and 4-dimethylaminopyridine (4.79 g) was added, and themixture was stirred at room temperature for 17 hours. After the reactionsolution was concentrated under reduced pressure, the obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=99:1 to 91:9) to obtain Compound 8 (40.68 g) as a colorless oil.

MS (m/z): 315 [M+H]⁺

(6)

A solution of diisopropyl amine (1.94 mL) in tetrahydrofuran (30 mL) wascooled to −70° C., 2.6M n-butyl lithium (5.3 mL) was added dropwise, andthe mixture was stirred at the same temperature for 10 minutes.Subsequently, the temperature was elevated to 0° C. The reactionsolution was again cooled to −70° C., and a solution of Compound 8 (2.9g) in tetrahydrofuran (10 mL) was added dropwise. After the mixture wasstirred at the same temperature for 10 minutes, the temperature waselevated to 0° C. The reaction solution was again cooled to −70° C., andmethoxymethyl chloride (1.4 mL) was added dropwise. After the mixturewas stirred at the same temperature for 30 minutes, the temperature waselevated to room temperature, and the mixture was stirred for 13 hours.To the reaction solution was added a saturated aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine. After the mixture was dried overanhydrous magnesium sulfate, and concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography to obtain a cis form of Compound 9 (1.5 g) as a colorlessoil.

MS (m/z): 359 [M+H]⁺

(7)

To Compound 9 (31.56 g) was added a 1M solution of n-tetrabutylammoniumfluoride in tetrahydrofuran (175 mL), and the mixture was stirred atroom temperature for 21 hours. Additionally, a 1M solution ofn-tetrabutylammonium fluoride in tetrahydrofuran (85 mL) was added, andthe mixture was stirred at room temperature for 4 hours. The reactionsolution was concentrated under reduced pressure, to the obtainedresidue was added a saturated aqueous ammonium chloride solution, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Theextract was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography to obtainCompound 10 (18.56 g) as a colorless oil.

MS (m/z): 245 [M+H]⁺

(8)

A solution of Compound 4 (150 mg), Compound 10 (126 mg),tributylphosphine (127 μL) and ADDP (130 mg) in tetrahydrofuran (3 mL)was heated at reflux overnight. The reaction solution was concentratedunder reduced pressure, and the residue was washed with diethyl etherand filtered. The filtrate was concentrated under reduced pressure, andthe obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 80:20) to obtain Compound 11 (162 mg) acolorless viscous material.

MS (m/z): 663 [M+H]⁺

(9)

Compound 11 (162 mg) was dissolved in trifluoroacetic acid (3 mL) andwater (0.3 mL), and the mixture was stirred at room temperatureovernight. The reaction solution was concentrated under reducedpressure, to the obtained residue was added acetic acid, and the mixturewas concentrated under reduced pressure. The residue was crystallizedfrom ethyl acetate, and the obtained solid was filtered and dried toobtain Compound 12 (96 mg) as an ivory solid.

MS (m/z): 477 [M+H]⁺

Example 54

(1)

A reaction was carried out in a manner similar to the Example 52-(6)using Compound 1 (207 mg) and Compound 2 (293 mg) to obtain Compound 3(252 mg) as a colorless solid.

MS (m/z): 552 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 52-(7)using Compound 3 (244 mg) to obtain Compound 4 (223 mg) as a colorlesssolid.

MS (m/z): 538 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 52-(8)using Compound 4 (216 mg) to obtain Compound 5 (157 mg) as a colorlesssolid.

MS (m/z): 408 [M+H]⁺

Example 55

(1)

A reaction was carried out in a manner similar to the Example 51-(2)using Compound 1 (1000 mg) and Compound 2 (702 mg) to obtain Compound 3(534 mg) as a colorless viscous material.

MS (m/z): 400/402 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 51-(4)using Compound 3 (200 mg) and a mixture of Compounds 4a and 4b (469 mg)to obtain Compound 5a (151 mg) and Compound 5b (104 mg) as colorlessviscous materials respectively.

MS (m/z): 663 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 53-(9)using a mixture of Compound 5a and Compound 5b (250 mg) to obtainCompound 6 (158 mg).

MS (m/z): 477 [M+H]⁺

Example 56

(1)

To Compound 2 (4.21 g) were added toluene (100 mL) and triethylamine(9.9 mL) at room temperature, and the mixture was stirred for 5 minutes.Subsequently, Compound 1 (5 g) was added, and the mixture was stirred atroom temperature for 5 days. The reaction solution was filtered throughCelite, and the filtrate was concentrated under reduced pressure. To theobtained residue were added carbon tetrachloride (66.4 mL) and hydrazinehydrate (1.42 mL), and the mixture was stirred at room temperatureovernight. The reaction solution was diluted with ethyl acetate andfiltered through Celite. The filtrate was concentrated under reducedpressure, to the obtained residue were added water, ethyl acetate and asaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was concentrated under reducedpressure, and the obtained residue was washed with diethyl ether andfiltered to obtain Compound 3 (928 mg) as a light pink powder.

MS (m/z): 195/197 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 50-(5)using Compound 3 (819 mg) to obtain a mixture of Compounds 4a and 4b(1.014 g) as colorless crystals.

MS (m/z): 325/327 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 52-(6)using the mixture of Compounds 4a and 4b (200 mg) and Compound 5 (309mg) to obtain Compound 6a (84 mg) and Compound 6b (78 mg) as colorlesspowders each.

MS (m/z): 521 [M+H]⁺

(4)

A reaction was carried out in a manner similar to the Example 52-(7)using Compound 6a (83 mg) to obtain Compound 7a (77 mg) as a colorlesspowder. Further, the similar reaction was carried out using Compound 6b(83 mg) to obtain Compound 7b (69 mg) as a colorless powder.

MS (m/z): 507 [M+H]⁺

(5)

A reaction was carried out in a manner similar to the Example 52-(8)using a mixture of Compounds 7a and 7b (146 mg) to obtain Compound 8 (94mg) a colorless powder.

MS (m/z): 377 [M+H]⁺

Example 57

Compound 1 (73 mg), EDC-HCl (88 mg), HOBt (62 mg), ammonium chloride (25mg) and triethylamine (64 μL) were dissolved in dimethylsulfoxide (1mL), and the mixture was stirred at room temperature overnight. To thereaction solution was added water, and the mixture was extracted withethyl acetate and washed with water. After the solution was dried andconcentrated under reduced pressure, the obtained residue was purifiedby silica gel column chromatography (chloroform:methanol=97:3 to 90:10)to obtain Compound 2 (46 mg) as a colorless solid.

MS (m/z): 476 [M+H]⁺

Example 58

(1)

A solution of Compound 1 (5 g) in tetrahydrofuran (96 mL) was cooled to−78° C., a solution of n-butyl lithium in n-hexane (18.3 mL) was addeddropwise over 10 minutes, and the mixture was stirred at the sametemperature for 20 minutes. Then, a solution of sec-butyl lithium inn-hexane (40.7 mL) was added dropwise over 10 minutes at the sametemperature, and the mixture was stirred at the same temperature for 1hour. Further, a solution of Compound 2 (6.73 g) in tetrahydrofuran (44mL) was added dropwise at the same temperature over 20 minutes, and themixture was stirred at the same temperature for 3 hours. To the reactionsolution was added dropwise a saturated aqueous ammonia chloridesolution (60 mL), and the temperature was elevated to room temperature.Water was added, the mixture was extracted with ethyl acetate, and theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. After the solution was concentrated under reducedpressure, the obtained residue was purified by silica gel columnchromatography (n-hexane:2-propanol=85:15 to 70:30 andchloroform:methanol=100:0 to 93:7) to obtain Compound 3 (2.207 g) as acolorless powder.

MS (m/z): 252 [M+H]⁺

(2)

To a solution of Compound 3 (1.944 g) in tetrahydrofuran (57 mL) wasadded the Burgess reagent, and the mixture was heated at reflux for 20hours. The reaction solution was ice cooled, an aqueous saturated sodiumhydrogen carbonate solution was added, and the mixture was extractedwith ethyl acetate. The extract was dried over anhydrous magnesiumsulfate and subsequently concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(n-hexane:2-propanol=91:9 to 80:20) to obtain Compound 4 (953 mg) as ayellow viscous material.

MS (m/z): 234 [M+H]⁺

(3)

To a solution of Compound 4 (953 mg) in methanol (33 mL) was addedpalladium carbon (286 mg), and the mixture was stirred under a hydrogenatmosphere at room temperature for 2.5 hours. The reaction solution wasfiltered, and the filtrate was concentrated under reduced pressure. Theobtained residue was washed with isopropyl ether to obtain Compound 5(627 mg) as a colorless powder.

MS (m/z): 236 [M+H]⁺

(4)

A solution of Compound 5 (915 mg) in tetrahydrofuran (4.2 mL) was icecooled, and sodium hydride (233 mg) was added, and the mixture wasstirred at the same temperature for 30 minutes. A solution of benzylbromide (509 μL) in dimethylsulfoxide (4.2 mL) was then added dropwiseat the same temperature, and the mixture was stirred at room temperaturefor 3 hours. To the reaction solution was added water, the mixture wasextracted with ethyl acetate, and the extract was washed with brine. Thesolution was dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure to obtain a yellow solid (1.45 g). This yellowsolid (1.26 g) was dissolved in tetrahydrofuran (38 mL), 2N hydrochloricacid (19 mL) was added, and the mixture was stirred at 50° C. for 19hours. The reaction solution was concentrated under reduced pressure,ethyl acetate was added, and the solution was neutralized with a 1Naqueous sodium hydroxide solution. The mixture was extracted with ethylacetate, and the extract was washed with brine and dried over anhydroussodium sulfate. The solution was concentrated under reduced pressure,and the obtained solid was washed with isopropyl ether and filtered. Theobtained powder was vacuum-dried at 50° C. to obtain Compound 6 (979 mg)as a pale yellow powder.

MS (m/z): 282 [M+H]⁺

(5)

A solution of Compound 7 (760 mg) in tetrahydrofuran (3 mL) was icecooled, and 60% sodium hydride (174 mg) was added, and the mixture wasstirred at room temperature for 30 minutes. Compound 6 (979 mg) was thenadded, and the mixture was stirred for 17 hours. The reaction solutionwas ice cooled, water was added, and the mixture was extracted withethyl acetate. The extract was washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The obtainedsolid was washed with isopropyl ether and collected by filtration. Thesolid was vacuum-dried at 50° C. to obtain Compound 8 (1.005 g) as apale yellow powder. Further, the filtrate was concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=80:20 to 67:33) to obtainCompound 8 (129 mg) as a pale yellow powder.

MS (m/z): 338 [M+H]⁺

(6)

To a solution of Compound 8 (1133 mg) of ethyl acetate (23 mL) was addedpalladium carbon (340 mg), and the mixture was stirred under a hydrogenatmosphere at room temperature for 3 days. The reaction solution wasfiltered, the filtrate was concentrated under reduced pressure, and theobtained residue was washed with diethyl ether and vacuum-dried at 50°C. to obtain Compound 9 (497 mg) as a pale yellow powder. Further, thefiltrate was concentrated and treated in a similar procedure to obtainCompound 9 (327 mg).

MS (m/z): 250 [M+H]⁺

(7)

A suspension of Compound 9 (824 mg) in methylene chloride (16 mL) wasice cooled, trifluoromethanesulfonic anhydride (695 μL) was added, andtriethylamine (691 μL) was then added, and the mixture was stirred atroom temperature for 16 hours. To the reaction solution was added anaqueous saturated sodium hydrogen carbonate solution, and the mixturewas extracted with methylene chloride. The extract was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=95:5 to 75:25) to obtain Compound 10 (1.214 g)as a pale yellow oil.

MS (m/z): 382 [M+H]⁺

(8)

Compound 10 (1214 mg), Compound 11 (889 mg),(diphenylphosphino)ferrocene (53 mg) and potassium acetate (937 mg) wereadded to 1,4-dioxane (16 mL), and the mixture was subjected to nitrogensubstitution. A [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (78 mg) was then added, and themixture was subjected to nitrogen substitution again, and stirred at 80°C. for 16 hours. To the reaction solution was added water and ethylacetate, and the mixture was stirred and filtered through Celite. Afterthe filtrate was extracted with ethyl acetate, the extract was washedwith saturated brine and dried. After concentration under reducedpressure, the obtained residue was purified by diol silica gel columnchromatography (n-hexane:ethyl acetate=83:17 to 67:33) to obtainCompound 12 (570 mg) as a pale yellow oil.

MS (m/z): 360 [M+H]⁺

(9)

A reaction was carried out in a manner similar to the Example 50-(6)using a mixture of Compounds 13a and 13b (250 mg) and Compound 12 (255mg) to obtain a mixture of Compounds 14a and 14b (199 mg) as a colorlessoil.

MS (m/z): 575 [M+H]⁺

(10)

A reaction was carried out in a manner similar to the Example 52-(7)using the mixture of Compounds 14a and 14b (199 mg) to obtain a mixtureof Compounds 15a and 15b (197 mg) as a pale yellow oil.

MS (m/z): 561 [M+H]⁺

(11)

A reaction was carried out in a manner similar to the Example 52-(8)using the mixture of Compounds 15a and 15b (196 mg) to obtain Compound16 (67 mg) of a colorless powder as a mixture of cis/trans forms.

MS (m/z): 431 [M+H]⁺

Example 59

(1)

A mixture of Compound 1 (500 mg), Compound 2 (458 mg), sodium methylate(821 mg) and ethanol (7 mL) was heated at reflux for 4 days. Thereaction solution was cooled and diluted with a saturated aqueousammonium chloride solution, and the deposit was collected by filtration,washed with water and then dried at 45° C. overnight. After drying, thesolid was dissolved in tetrahydrofuran, and dried over potassiumcarbonate, then concentrated under reduced pressure to obtain Compound 3(505 mg) as a pale yellow solid.

MS (m/z): 300/302 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 50-(5)using Compound 1 (505 mg) to obtain a mixture of Compounds 2a and 2b(397 mg) as a pale yellow oil.

MS (m/z): 430/432 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 51-(3)using Compound 3 (1011 mg) to obtain Compound 5 (952 mg) as a colorlesssolid.

MS (m/z): 378 [M+H]⁺

(4)

A reaction was carried out in a manner similar to the Example 51-(4)using the mixture of Compounds 2a and 2b (300 mg) to obtain a mixture ofCompounds 6a and 6b (298 mg) as a pale yellow oil.

MS (m/z): 601 [M+H]⁺

(5)

A reaction was carried out in a manner similar to the Example 51-(5)using the mixture of Compounds 6a and 6b (298 mg) to obtain Compound 7(186 mg) as an ivory solid.

MS (m/z): 415 [M+H]⁺

Example 60

(1)

Benzotriazole (112.5 g) was dissolved in ethanol (2 L), and a solutionof cyano bromide (50 g) in acetone (200 mL) was added dropwise under icecooling. An aqueous solution of sodium hydroxide (18.9 g) dissolved inwater (170 mL) was then added dropwise, and the mixture was stirred atthe same temperature for 15 minutes. The deposit was filtered, washedwith cold ethanol and subsequent dried to obtain Compound 1 (71.21 g) asa colorless solid.

MS (m/z): 264 [M+H]⁺

(2)

To a solution of Compound 1 (1000 mg) in tetrahydrofuran (20 mL) wereadded Compound 2 (599 mg) and triethylamine (529 μL), and the mixturewas stirred at room temperature overnight. The reaction solution wasconcentrated under reduced pressure, to the residue were added methylenechloride and an aqueous potassium carbonate solution, and the organiclayer was separated, washed with saturated brine, and concentrated underreduced pressure. To the residue was added 20 mL of chloroform, andCompound 3 (834 mg) and triethylamine (529 μL) were added under icecooling, and the mixture was stirred at room temperature overnight. Thereaction solution was extracted with chloroform, and the extract waswashed with saturated brine, and dried over anhydrous sodium sulfate.After the solution was concentrated under reduced pressure, the obtainedresidue was purified by silica gel column chromatography(n-hexane:2-propanol=97:3 to 55:45) to obtain Compound 4 (311 mg) as acolorless solid.

MS (m/z): 448/450 [M+H]⁺

(3)

To a solution of Compound 4 (311 mg) in chloroform (6 mL) was addedhydrazine hydrate (22 μL), and the mixture was stirred at roomtemperature overnight. The reaction solution was concentrated underreduced pressure, and the residue was dissolved in N,N-dimethylformamide(6 mL), and ice-cooled. To this was added sodium hydride (69 mg), andthe mixture was stirred at room temperature for 1 hour. The reactionsolution was ice-cooled, and (trimethylsilyl)ethoxymethyl chloride (307μL) was added dropwise. The temperature of the reaction solution waselevated to room temperature, and the reaction solution was stirred for3 days. To the reaction solution was added a saturated aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. After the solution was concentrated under reduced pressure, theobtained residue was purified by silica gel column chromatography(n-hexane:2-propanol=99:1 to 85:15) to obtain a mixture of Compounds 5aand 5b (125 mg) as a colorless oil.

MS (m/z): 473/475 [M+H]⁺

(4)

After the reaction was carried out in a manner similar to the Example50-(6) using the mixture of Compounds 5a and 5b (125 mg) and Compound 6(150 mg), the reaction solution was filtered through silica gel, andwashed with ethyl acetate. The filtrate was concentrated under reducedpressure, to the residue were added trifluoroacetic acid (5 mL) andwater (0.5 mL), and the mixture was stirred at room temperatureovernight. The reaction solution was concentrated, the residue wasdissolved by adding acetic acid thereto, and the solution wasconcentrated again under reduced pressure. The obtained residue waspurified by LC-MS to obtain Compound 8 (32 mg) as a beige solid.

MS (m/z): 458 [M+H]⁺

Example 61

(1)

To a solution of Compound 1 (2.00 g) in 1,4-dioxane (20 mL) was added anaqueous sodium hydrogen carbonate solution prepared from sodium hydrogencarbonate (781 mg) and water (15 mL), and the mixture was stirred atroom temperature for 5 minutes. To this was added cyano bromide (985mg), and the mixture was stirred at room temperature for 2 hours andthen at elevated temperature of 65° C. for two days. The obtainedcrystals were collected by filtration, sequentially washed with waterand diethyl ether, and dried to obtain Compound 2 (1.81 g) as acolorless solid.

MS (m/z): 240/242 [M+H]⁺

(2)

Compound 2 (500 mg) was dissolved in ethanol (15 mL), potassiumhydroxide (467 mg) was added, and at the temperature of 90° C., and themixture was stirred for 8 hours. After the mixture was allowed to coolto room temperature, it was neutralized by addition of a 2N aqueoushydrochloric acid solution. Ethyl acetate and water were added to thereaction solution to carry out a liquid separation. The organic layerwas separated, washed with saturated brine, passed through the phaseseparator and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography(chloroform:methanol=100:0 to 93:7) to obtain Compound 3 (396 mg) as acolorless solid.

MS (m/z): 268/270 [M+H]⁺

(3)

To a solution of Compound 3 (500 mg) dissolved in N,N-dimethylformamide(5 mL) was added 60% sodium hydride (112 mg) under a nitrogen atmosphereunder ice cooling, and the mixture was stirred for 15 minutes.2-(Trimethylsilyl)ethoxymethyl chloride (491 μL) was added underice-cooling, and the mixture was stirred for 1 hour. To the reactionsolution was added a saturated aqueous ammonium chloride solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, passed through the phase separator andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=99:1 to60:40) to obtain a mixture of Compounds 4a and 4b (773 mg) as a paleyellow powder.

MS (m/z): 398/400 [M+H]⁺

(4)

A solution of the mixture of Compounds 4a and 4b (740 mg), palladiumacetate (21 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (76mg), Compound 5 (747 mg) and tripotassium phosphate (789 mg) intetrahydrofuran (10 mL) was stirred at the temperature of 50° C. under anitrogen atmosphere overnight. After the reaction solution was allowedto cool to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was stirred. Ethyl acetatewas added to carry out a liquid separation. The organic layer was washedwith saturated brine, passed through the phase separator andconcentrated under reduced pressure. To the obtained residue were addedtrifluoroacetic acid (3 mL) and water (0.15 mL), and the mixture wasstirred at room temperature overnight. To the reaction solution wasadded a 2N aqueous sodium hydroxide solution to adjust the pH to about 2to 3, and ethyl acetate was added to carry out a liquid separation. Theorganic layer was separated, washed with saturated brine, passed throughthe phase separator and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=80:20 to 50:50) to obtain Compound 6 (351 mg) asa pale yellow viscous material.

MS (m/z): 397 [M+H]⁺

(5)

Compound 6 (348 mg) were dissolved in tetrahydrofuran (2 mL) andmethanol (2 mL), a 2N aqueous sodium hydroxide solution (3 mL) wasadded, and the mixture was stirred at 50° C. for 2 hours. After thereaction solution was neutralized by addition of 2N hydrochloric acid,ethyl acetate was added to carry out a liquid separation. The organiclayer was separated, washed with saturated brine, passed through thephase separator, and concentrated under reduced pressure. The obtainedresidue was triturated with addition of dichloromethane and a smallamount of methanol, and collected by filtration to obtain Compound 7(186 mg) as a colorless solid.

MS (m/z): 383 [M+H]⁺

Example 62

(1)

A treatment was carried out in a manner similar to the Example 61-(2)using Compound 1 (2.00 g) and 2-propanol (60 mL) to obtain Compound 2(618 mg) as a colorless solid.

MS (m/z): 282/284 [M+H]⁺

(2)

Starting from Compound 2 (610 mg), a treatment was carried out in amanner similar to the Example 61-(3) to obtain a mixture of Compounds 3aand 3b (476 mg) as a colorless solid.

MS (m/z): 412/414 [M+H]⁺

(3)

A solution of the mixture of Compounds 3a and 3b (473 mg), palladiumacetate (13 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (47mg), Compound 4 (461 mg) and tripotassium phosphate (487 mg) intetrahydrofuran (6 mL) was stirred at the temperature of 70° C. under anitrogen atmosphere overnight. After the reaction solution was allowedto cool to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixturewas stirred. Ethyl acetate was added to carry out a liquid separation.The organic layer was washed with saturated brine, passed through thephase separator and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=98:2 to 65:35) to obtain a mixture of Compounds 5a and 5b (460mg) as a pale yellow viscous material.

MS (m/z): 541 [M+H]⁺

(4)

To the mixture of Compounds 5a and 5b (460 mg) were addedtrifluoroacetic acid (2 mL) and water (0.1 mL), and the mixture wasstirred at room temperature overnight. To the reaction solution wasadded a 2N aqueous sodium hydroxide solution to adjust the pH to about 2to 3, and ethyl acetate was added to carry out a liquid separation. Theorganic layer was separated, washed with saturated brine, passed throughthe phase separator and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=80:20 to 50:50) to obtain Compound 6 (144 mg) asa colorless viscous material.

MS (m/z): 411 [M+H]⁺

(5)

Starting from Compound 6 (143 mg), a treatment was carried out in amanner similar to the Example 61-(5) to obtain Compound 7 (124 mg) as acolorless solid.

MS (m/z): 397 [M+H]⁺

Example 63

(1)

Starting from a mixture of Compounds 1a and 1b (500 mg) and Compound 2(526 mg), a treatment was carried out in a manner similar to the Example62-(3) to obtain a mixture of Compounds 3a and 3b (355 mg) as a paleyellow viscous material.

MS (m/z): 541 [M+H]⁺

(2)

Starting from a mixture of Compounds 3a and 3b (352 mg), a treatment wascarried out in a manner similar to the Example 62-(4) to obtain Compound4 (43.5 mg) as a colorless viscous material.

MS (m/z): 411 [M+H]⁺

(3)

Starting from Compound 4 (43.0 mg), a treatment was carried out in amanner similar to the Example 61-(5) to obtain Compound 5 (32.9 mg) as awhite solid.

MS (m/z): 397 [M+H]⁺

Example 64

(1)

Starting from a mixture of Compounds 1a and 1b (500 mg) and Compound 2(526 mg), a treatment was carried out in a manner similar to the Example62-(3) to obtain a mixture of Compounds 3a and 3b (708 mg) as a paleyellow viscous material.

MS (m/z): 541 [M+H]⁺

(2)

Starting from a mixture of Compounds 3a and 3b (705 mg), a treatment wascarried out in a manner similar to the Example 62-(4) to obtain Compound4 (480 mg) as a colorless viscous material.

MS (m/z): 411 [M+H]⁺

(3)

Starting from Compound 4 (478 mg), a treatment was carried out in amanner similar to the Example 61-(5) to obtain Compound 5 (288 mg) as acolorless solid.

MS (m/z): 397 [M+H]⁺

Example 65

(1)

Starting from a mixture of Compounds 1a and 1b (500 mg) and Compound 2(526 mg), a treatment was carried out in a manner similar to the Example62-(3) to obtain a mixture of Compounds 3a and 3b (723 mg) as a paleyellow viscous material.

MS (m/z): 526 [M+H]⁺

(2)

Starting from a mixture of Compounds 3a and 3b (720 mg), a treatment wascarried out in a manner similar to the Example 62-(4) to obtain Compound4 (463 mg) as a colorless solid.

MS (m/z): 396 [M+H]⁺

(3)

Starting from Compound 4 (463 mg), a treatment was carried out in amanner similar to the Example 61-(5) to obtain Compound 5 (356 mg) as acolorless solid.

MS (m/z): 382 [M+H]⁺

Example 66

(1)

Starting from a mixture of Compounds 1a and 1b (1500 mg) and Compound 2(1035 mg), a treatment was carried out in a manner similar to theExample 62-(3) to obtain a mixture of Compounds 3a and 3b (1226 mg) as awhite solid.

MS (m/z): 503 [M+H]⁺

(2)

To a mixture of Compounds 3a and 3b (1220 mg) were added methanol (20mL) and tetrahydrofuran (20 mL), 10% palladium carbon (244 mg) was addedunder a hydrogen atmosphere, and the mixture was stirred at roomtemperature for 6 hours. After the catalyst was filtered off over amembrane filter, the filtrate was concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (chloroform:methanol=100:0 to 93:7) to obtain a mixtureof Compounds 4a and 4b (902 mg) as a colorless viscous material.

MS (m/z): 413 [M+H]⁺

(3)

To a solution of a mixture of Compounds 4a and 4b (500 mg) in methylenechloride (10 mL) was added triethylamine (0.34 mL),trifluoromethanesulfonic anhydride (0.24 mL) was added dropwise underice cooling, and the mixture was stirred for 1 hour. A saturated aqueoussodium hydrogen carbonate solution was added to carry out extraction.The organic layer was separated, washed with saturated brine, passedthrough the phase separator and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 65:35) to obtain Compounds 5a and 5b(542 mg) as a colorless solid.

MS (m/z): 545 [M+H]⁺

(4)

Starting from a mixture of Compounds 5a and 5b (535 mg) and Compound 6(330 mg), a treatment was carried out in a manner similar to the Example62-(3) to obtain a mixture of Compounds 7a and 7b (382 mg) as a paleyellow viscous material.

MS (m/z): 549 [M+H]⁺

(5)

Starting from a mixture of Compounds 7a and 7b (382 mg), a treatment wascarried out in a manner similar to the Example 62-(4) to obtain Compound8 (277 mg) as a colorless solid.

MS (m/z): 419 [M+H]⁺

(6)

To a suspension of Compound 7 (250 mg) in methanol (4 mL) andtetrahydrofuran (4 mL) was added 10% palladium carbon (50 mg) under anitrogen atmosphere, and the mixture was subjected to hydrogensubstitution and stirred under a hydrogen atmosphere at room temperaturefor 4 hours. The reaction solution was filtered and concentrated underreduced pressure to obtain a mixture of geometrical isomers of Compound8 (219 mg) as a colorless liquid.

MS (m/z): 421 [M+H]⁺

(7)

Starting from Compound 8 (218 mg), a treatment was carried out in amanner similar to the Example 61-(5) to obtain a mixture of geometricalisomers of Compound 9 (199 mg) as a colorless solid.

MS (m/z): 407 [M+H]⁺

Example 67

(1)

To a solution of a mixture of Compounds 1a and 1b (400 mg), Compound 2(200 mg) and triphenylphosphine (763 mg) in tetrahydrofuran (8 mL) wereadded dropwise a 40 wt % solution of diethyl azodicarboxylate in toluene(1324 μL) under ice cooling, and the mixture was stirred at 70° C.overnight. After the mixture was allowed to cool to room temperature,the residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography (n-hexane:ethylacetate=83:17 to 50:50) to obtain a mixture of Compounds 3a and 3b (421mg) as a colorless viscous material.

MS (m/z): 567 [M+H]⁺

(2)

A mixture of Compounds 3a and 3b (415 mg) was treated in a mannersimilar to the Example 62-(4) to obtain Compound 4 (328 mg) as acolorless viscous material.

MS (m/z): 437 [M+H]⁺

(3)

Compound 4 (324 mg) was treated in a manner similar to the Example61-(5) to obtain Compound 5 (183 mg) as a colorless solid.

MS (m/z): 409 [M+H]⁺

Example 68

(1)

To a solution of Compound 1 (19.0 g), carbon disulfide (22.9 mL) andmethyl iodide (17.7 mL) in tetrahydrofuran (380 mL) was added sodiumhydride (7.6 g) at 0° C., the temperature was brought to roomtemperature, and the mixture was stirred for 8 hours. Water and ethylacetate were added and stirred to carry out a liquid separation. Theorganic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=98:2 to 85:15) to obtain Compound 2 (10.8 g) asa pale yellow solid.

MS (m/z): 304/306 [M+H]⁺

(2)

To a solution of Compound 2 (10.8 g) in methanol (50 mL) andtetrahydrofuran (50 mL) was added dropwise hydrazine.monohydrate (1.90mL), and the mixture was stirred at room temperature for 1 hour. Afterthe solvent was distilled off, to the residue was added diethyl ether,and the mixture was stirred. The crystals was collected by filtrationand vacuum-dried to obtain Compound 3 (9.13 g) as a colorless solid.

MS (m/z): 270/272 [M+H]⁺

(3)

Compound 3 (7 g) was treated in a manner similar to the Example 61-(3)to obtain Compound 4a (6.53 g) and Compound 4b (3.02 g) as a colorlessviscous material and a colorless solid, respectively.

MS (m/z): 400/402 [M+H]⁺

(4)

To a solution of Compound 4a (6.53 g) in methylene chloride (80 mL) wasadded 3-chloroperbenzoic acid (11.2 g) at 0° C., and the mixture wasstirred at room temperature for 2 hours. A saturated aqueous sodiumhydrogen carbonate solution was added, and the mixture was stirred andextracted with methylene chloride. The organic layer was separated,washed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=92:8 to80:20) to obtain Compound 5 (7.44 g) as a colorless solid.

MS (m/z): 432/434 [M+H]⁺

(5)

To a solution of sodium hydride (14.6 mg) in tetrahydrofuran (0.5 mL)was added dropwise 2,2,2-trifluoroethanol 6 (26.1 μL) under ice cooling,and the mixture was stirred at the same temperature for 15 minutes. Tothis was added a solution of Compound 5 (79 mg) in tetrahydrofuran (1.5mL), and the mixture was stirred at room temperature for 2 hours. Asaturated aqueous ammonium chloride solution was added, and the mixturewas stirred. Subsequently, water and ethyl acetate were added andstirred to carry out a liquid separation. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=98:2 to 92:8) to obtain Compound 7 (77.3 mg) as a colorlesssolid.

MS (m/z): 452/454 [M+H]⁺

(6)

To a solution of Compound 7 (75 mg), a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (6.8 mg) and Compound 8 (67 mg) inN,N-dimethylformamide (1 mL) was added dropwise a 2N aqueous sodiumcarbonate solution (249 μL) under a nitrogen stream, and the mixture wasstirred at 60° C. for 6 hours. After the mixture was cooled to roomtemperature, water and ethyl acetate were added and stirred to carry outa liquid separation. The organic layer was separated, washed withsaturated brine, passed through the phase separator, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=95:5 to 85:15) to obtainCompound 9 (74.3 mg) as a colorless viscous material.

MS (m/z): 581 [M+H]⁺

(7)

To Compound 9 (73 mg) were added trifluoroacetic acid (1 mL) and water(0.05 mL), and the mixture was stirred at room temperature for 6 hours.A 2N aqueous sodium hydroxide solution was added to adjust the pH toabout 2-3, and an extraction with ethyl acetate was carried out. Theorganic layer was separated, washed with saturated brine, passed throughthe phase separator, and concentrated under reduced pressure. To theobtained residue were added methanol (0.5 mL), tetrahydrofuran (0.5 mL)and a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture wasstirred at 50° C. for 2 hours. After the mixture was neutralized withaddition of ethyl acetate and a 1N aqueous hydrochloric acid solution,an extraction was carried out. The organic layer was separated, washedwith saturated brine, passed through the phase separator, andconcentrated under reduced pressure. To the obtained residue was addeddiethyl ether, and the mixture was stirred. The obtained crystals werecollected by filtration and vacuum-dried to obtain Compound 10 (34 mg)as a colorless solid.

MS (m/z): 437 [M+H]⁺

Example 69

(1)

Starting from Compound 1 (5.00 g) and Compound 2 (4.65 g), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (4.45 g) as a pale yellow powder.

MS (m/z): 561 [M+H]⁺

(2)

A suspension of Compound 3 (48 mg), Compound 4 (19.2 mg) and sodiumcarbonate (59 mg) in N-methylpyrrolidone (0.5 mL) was stirred at 120° C.for 1 hour. After the mixture was cooled to room temperature, water andethyl acetate were added and stirred to carry out a liquid separation.The organic layer was separated, washed with saturated brine, passedthrough the phase separator and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=88:12 to 70:30) to obtain Compound 5 (40 mg) asa colorless viscous material.

MS (m/z): 593 [M+H]⁺

(3)

Starting from Compound 5 (21.0 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 6 (11.8 mg) as acolorless solid.

MS (m/z): 449 [M+H]⁺

(4)

To a suspension of Compound 6 (266 mg) in acetonitrile (2 mL) was addeddropwise a 1N aqueous sodium hydroxide solution (593 μL), and themixture was stirred at room temperature for 8 hours. After the solventwas distilled off under reduced pressure, the residue crystals weretriturated with diethyl ether, collected by filtration and vacuum-driedto obtain Compound 7 (253 mg) as a colorless solid.

MS (m/z): 447 [M−Na]⁻

Example 70

(1)

Starting from Compound 1 (400 mg) and Compound 2 (186 mg), a treatmentwas carried out in a manner similar to the Example 69-(2) to obtainCompound 3 (363 mg) as a colorless viscous material.

MS (m/z): 611 [M+H]⁺

(2)

Starting from Compound 3 (360 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (205 mg) as acolorless solid.

MS (m/z): 467 [M+H]⁺

Example 71

(1)

Starting from Compound 1 (400 mg) and Compound 2 (186 mg), a treatmentwas carried out in a manner similar to the Example 69-(2) to obtainCompound 3 (403 mg) as a colorless viscous material.

MS (m/z): 611 [M+H]⁺

(2)

Starting from Compound 3 (400 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (220 mg) as acolorless solid.

MS (m/z): 467 [M+H]⁺

Example 72

(1)

Starting from Compound 1 (100 mg) and Compound 2 (33.9 mg), a treatmentwas carried out in a manner similar to the Example 69-(2) to obtainCompound 3 (83 mg) as a colorless viscous material.

MS (m/z): 576 [M+H]⁺

(2)

Starting from Compound 3 (82 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (52 mg) as acolorless solid.

MS (m/z): 432 [M+H]⁺

Example 73

(1)

Starting from Compound 1 (400 mg) and Compound 2 (163 mg), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 3 (262 mg) as a colorless viscous material.

MS (m/z): 595 [M+H]⁺

(2)

Starting from Compound 3 (260 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (157 mg) as acolorless solid.

MS (m/z): 451 [M+H]⁺

Example 74

(1)

Starting from Compound 1 (400 mg) and Compound 2 (214 mg), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 3 (406 mg) as a colorless solid.

MS (m/z): 631 [M+H]⁺

(2)

To the carboxylic acid compound synthesized from Compound 3 (402 mg) bytreating it in a manner similar to the Example 68-(7) were added 1 mL ofacetonitrile and an equal amount of a 1 N aqueous sodium hydroxidesolution, and additionally diethyl ether was added until completedissolution. After the solvent was distilled off under reduced pressure,the residue was stirred in a small amount of ethyl acetate and diethylether, and the crystals were collected by filtration and dried underreduced pressure to obtain Compound 4 (271 mg) as a colorless solid.

MS (m/z): 485 [M−Na]⁻

Example 75

(1)

Starting from Compound 1 (300 mg) and Compound 2 (128 mg), a treatmentwas carried out in a manner similar to the Example 69-(2) to obtainCompound 3 (144 mg) as a colorless viscous material.

MS (m/z): 600 [M+H]⁺

(2)

Starting from Compound 3 (142 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (57 mg) as acolorless solid.

MS (m/z): 456 [M+H]⁺

Example 76

(1)

Starting from Compound 1 (100 mg) and Compound 2 (33.9 mg), a treatmentwas carried out in a manner similar to the Example 69-(2) to obtainCompound 3 (13.9 mg) as a colorless solid.

MS (m/z): 576 [M+H]⁺

(2)

Starting from Compound 3 (30 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (18.7 mg) as acolorless solid.

MS (m/z): 432 [M+H]⁺

Example 77

(1)

From Compound 1 (200 mg) and Compound 2 (77.8 mg), a treatment wascarried out in a manner similar to the Example 69-(2) to obtain Compound3 (38 mg) as a colorless solid.

MS (m/z): 590 [M+H]⁺

(2)

Starting from Compound 3 (36 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (24.8 mg) as acolorless solid.

MS (m/z): 446 [M+H]⁺

Example 78

(1)

To a solution of Compound 1 (3.00 g) and potassium carbonate (311 mg) indimethylsulfoxide (45 mL) was added an aqueous 30% hydrogen peroxidesolution (1.7 mL) under ice cooling, and the mixture was stirred at roomtemperature overnight. To this was added an additional aqueous 30%hydrogen peroxide solution (0.5 mL), and the mixture was further stirredat room temperature for 4 days. Water was slowly added dropwise, and theobtained crystals were collected by filtration, washed with diethylether and subsequently vacuum-dried to obtain Compound 2 (1284 mg) as acolorless solid.

MS (m/z): 218/220 [M+H]⁺

(2)

Starting from Compound 2 (1200 mg), a treatment was carried out in amanner similar to the Example 68-(1) to obtain Compound 3 (621 mg) as apale yellow solid.

MS (m/z): 322/324 [M+H]⁺

(3)

Starting from Compound 3 (640 mg), a treatment was carried out in amanner similar to the Example 68-(2) to obtain Compound 4 (479 mg) as acolorless solid.

MS (m/z): 288/290 [M+H]⁺

(4)

Starting from Compound 4 (445 mg), a treatment was carried out in amanner similar to the Example 61-(3) to obtain Compound 5a (328 mg) andCompound 5b (351 mg) both as colorless viscous materials.

Compound 5a: MS (m/z): 418/420 [M+H]⁺

Compound 5b: MS (m/z): 418/420 [M+H]⁺

(5)

Starting from Compound 5a (325 mg), a treatment was carried out in amanner similar to the Example 68-(4) to obtain Compound 6a (331 mg) as acolorless viscous material.

MS (m/z): 450/452 [M+H]⁺

(6)

Starting from Compound 6a (330 mg) and Compound 7 (112 μL), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 8a (265 mg) as a colorless viscous material.

MS (m/z): 430/432 [M+H]⁺

(7)

Starting from Compound 8a (260 mg) and Compound 9 (253 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 10a (333 mg) as a colorless viscous material.

MS (m/z): 573 [M+H]⁺

(8)

Starting from Compound 10a (330 mg), a treatment was carried out in amanner similar to the Example 62-(4) to obtain Compound 11 (167 mg) as acolorless viscous material.

MS (m/z): 443 [M+H]⁺

(9)

Starting from Compound 11 (166 mg), a treatment was carried out in amanner similar to the Example 61-(5) to obtain Compound 12 (132 mg) as acolorless solid.

MS (m/z): 429 [M+H]⁺

Example 79

(1)

Starting from Compound 1 (3000 mg), a treatment was carried out in amanner similar to the Example 78-(1) to obtain Compound 2 (2842 mg) as acolorless solid.

MS (m/z): 201/203 [M+H]⁺

(2)

Starting from Compound 2 (2800 mg), a treatment was carried out in amanner similar to the Example 68-(1) to obtain Compound 3 (257 mg) as apale yellowish-orange solid.

MS (m/z): 305/307 [M+H]⁺

(3)

Starting from Compound 3 (255 mg), a treatment was carried out in amanner similar to the Example 68-(2) to obtain Compound 4 (166 mg) apale yellow solid.

MS (m/z): 271/273 [M+H]⁺

(4)

Starting from Compound 5 (162 mg), a treatment was carried out in amanner similar to the Example 61-(3) to obtain Compound 6a (92.9 mg) asa colorless viscous material and Compound 6b (89.1 mg) as a pale yellowsolid, respectively.

Compound 6a: MS (m/z): 401/403 [M+H]⁺

Compound 6b: MS (m/z): 401/403 [M+H]⁺

(5)

To a solution of Compound 6b (88.0 mg) in methylene chloride (1 mL) wasadded acetic acid (50 μL), 3-chloroperbenzoic acid (151 mg) was addedunder ice cooling, and the mixture was stirred at room temperature for 3hours. A saturated aqueous sodium hydrogen carbonate solution was added,and the mixture was stirred and extracted with methylene chloride. Theorganic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=85:15 to 66:34) to obtain Compound 7b (53.2 mg)as a pale yellowish-orange solid.

MS (m/z): 433/435 [M+H]⁺

(6)

Starting from Compound 7b (53.0 mg) and Compound 8 (19 μL), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 9b (27.0 mg) as a colorless viscous material.

MS (m/z): 413/415 [M+H]⁺

(7)

Starting from Compound 9b (26.0 mg) and Compound 10 (43.9 mg), atreatment was carried out in a manner similar to the Example 68-(6) toobtain Compound 11b (31.6 mg) as a colorless viscous material.

MS (m/z): 556 [M+H]⁺

(8)

Starting from Compound 11b (31.0 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 12 (13.8 mg) asa colorless solid.

MS (m/z): 412 [M+H]⁺

Example 80

(1)

Starting from Compound 1 (2000 mg), a treatment was carried out in amanner similar to the Example 68-(1) to obtain Compound 2 (1153 mg) as awhite solid.

MS (m/z): 261/263 [M+H]⁺

(2)

Starting from Compound 2 (1150 mg), a treatment was carried out in amanner similar to the Example 68-(2) to obtain Compound 3 (829 mg) as acolorless solid.

MS (m/z): 227/229 [M+H]⁺

(3)

Starting from Compound 3 (500 mg), a treatment was carried out in amanner similar to the Example 61-(3) to obtain Compound 4a (478 mg) andCompound 4b (215 mg) both as colorless viscous materials.

Compound 4a: MS (m/z): 357/359 [M+H]⁺

Compound 4b: MS (m/z): 357/359 [M+H]⁺

(4)

Starting from Compound 4a (470 mg), a treatment was carried out in amanner similar to the Example 79-(5) to obtain Compound 5a (363 mg) as acolorless viscous material.

MS (m/z): 389/391 [M+H]⁺

(5)

Starting from Compound 5a (360 mg) and Compound 6 (141 μL), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 7a (272 mg) as a colorless solid.

MS (m/z): 369/371 [M+H]⁺

(6)

Starting from Compound 7a (200 mg) and Compound 8 (454 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 9a (258 mg) as a colorless viscous material.

MS (m/z): 556 [M+H]⁺

(7)

Starting from Compound 9a (254 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 10 (156 mg) as acolorless solid.

MS (m/z): 412 [M+H]⁺

Example 81

(1)

A reaction was carried out in a manner similar to the Example 68-(6)using Compound 2 (400 mg) and a mixture of Compounds 1a and 1b (363 mg)to obtain a mixture of Compounds 3a and 3b (379 mg) as a colorlessviscous material.

MS (m/z): 565 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 52-(7)using the mixture of Compounds 3a and 3b (375 mg) to obtain a mixture ofCompounds 4a and 4b (366 mg) as a colorless viscous material.

MS (m/z): 551 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 52-(8)using the mixture of Compounds 4a and 4b (363 mg) to obtain Compound 5(218 mg) as a colorless solid.

MS (m/z): 421 [M+H]⁺

Example 82

(1)

Starting from Compound 1 (500 mg), a treatment was carried out in amanner similar to the Example 68-(5) to obtain Compound 3 (343 mg) as acolorless solid.

MS (m/z): 470/472 [M+H]⁺

(2)

Starting from Compound 3 (341 mg) and Compound 4 (304 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 5 (436 mg) as a colorless viscous material.

MS (m/z): 613 [M+H]⁺

(3)

Starting from Compound 5 (435 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 6 (290 mg) as acolorless solid.

MS (m/z): 469 [M+H]⁺

Example 83

(1)

Starting from Compound 1 (500 mg), a treatment was carried out in amanner similar to the Example 69-(2) to obtain Compound 3 (357 mg) as acolorless viscous material.

MS (m/z): 482/484 [M+H]⁺

(2)

Starting from Compound 3 (355 mg) and Compound 4 (308 mg), a treatmentwas carried out in a manner similar to Example 68-(6) to obtain Compound5 (464 mg) as a colorless viscous material.

MS (m/z): 625 [M+H]⁺

(3)

Starting from Compound 5 (450 mg), a treatment was carried out in amanner similar to Example 68-(7) to obtain Compound 6 (293 mg) as acolorless solid.

MS (m/z): 481 [M+H]⁺

Example 84

(1)

Under ice cooling, to a solution of Compound 1 (2 g) in tetrahydrofuran(10 mL) was added dropwise a 1.6M lithiumbis(trimethylsilyl)amide/tetrahydrofuran solution (7.5 mL), and themixture was stirred at room temperature for 3 hours. The reactionsolution was ice cooled, and 4N hydrogen chloride-1,4-dioxane (6.2 mL)was added. Diethyl ether was added, and the deposit was collected byfiltration. The filtrate was concentrated under reduced pressure, andthe deposit was washed with diethyl ether and collected by filtration.The obtained deposits were combined to be used for the next reaction. Asolution of Compound 3 (0.75 mL) and hydrazine hydrate (0.29 mL) intetrahydrofuran (8 mL) was stirred at 65° C. for 1 hour. The reactionsolution was cooled to room temperature, the deposit obtained above wasadded, and the mixture was stirred at 65° C. for 2 hours. To thereaction solution was added water, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=100:0 to 80:20) to obtain Compound 5 (165 mg) asa colorless solid.

MS (m/z): 310/312 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 50-(5)using Compound 5 (164 mg) to obtain a mixture of Compounds 6a and 6b(228 mg) as a colorless viscous material.

MS (m/z): 440/442 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 50-(6)using the mixture of Compounds 6a and 6b (220 mg), and Compound 7 (174mg) to obtain a mixture of Compounds 8a and 8b (263 mg) as a colorlessviscous material.

MS (m/z): 583 [M+H]⁺

(4)

A reaction was carried out in a manner similar to the Example 52-(7)using the mixture of Compounds 8a and 8b (260 mg) to obtain a mixture ofCompounds 9a and 9b (259 mg) as a colorless viscous material.

MS (m/z): 569 [M+H]⁺

(5)

A reaction was carried out in a manner similar to the Example 52-(8)using Compounds 9a and 9b (254 mg) to obtain Compound 10 (130 mg) as acolorless solid.

MS (m/z): 439 [M+H]⁺

Example 85

(1)

To a solution of Compound 1 (10 g) in methylene chloride (200 mL) wereadded oxalyl chloride (4.43 mL) and N,N-dimethylformamide (0.16 mL) atroom temperature, and the mixture was stirred at room temperature for 2hours. The reaction solution was concentrated under reduced pressure,the residue was dissolved in tetrahydrofuran (50 mL), and this was addeddropwise to a suspension of thiosemicarbazide (3.85 g) and pyridine (75mL) under ice cooling over 10 minutes. After dropwise addition, themixture was stirred at room temperature for 2 hours and concentratedunder reduced pressure. The residue was dissolved in a 2N aqueous sodiumhydroxide solution (210 mL), and heated at reflux for 16 hours. Thereaction solution was ice cooled and neutralized with concentratedhydrochloric acid (35 mL). The deposit was collected by filtration andwashed with water and methanol. The obtained solid was suspended andwashed in diethyl ether (50 mL), collected by filtration and dried at50° C. under reduced pressure to obtain Compound 2 (9.46 g) as a beigesolid.

MS (m/z): 291/293/295 [M+H]⁺

(2)

Compound 2 (9.44 g) was suspended in ethanol (24 mL), and a 2N aqueoussodium hydroxide solution (17.8 mL) and methyl iodide (2.2 mL) wereadded at room temperature. After the reaction solution was stirred atroom temperature for 30 minutes, the deposit was collected byfiltration, washed with ethanol and vacuum-dried at 50° C. to obtainCompound 3 (7.815 g) as a beige solid.

MS (m/z): 305/307/309 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 61-(3)using Compound 3 (7.815 g) to obtain Compound 4a (7.335 g) and Compound4b (4.294 g) as yellow viscous materials respectively.

MS (m/z): 435/437/439 [M+H]⁺

(4)

A reaction was carried out in a manner similar to the Example 68-(4)using Compound 4b (3.69 g) to obtain Compound 5 (3.323 g) as a colorlesssolid.

MS (m/z): 466/468/470 [M+H]⁺

(5)

A reaction was carried out in a manner similar to the Example 68-(5)using Compound 5 (1 g) to obtain Compound 6 (826 mg) as a colorlessviscous material.

MS (m/z): 447/449/451 [M+H]⁺

(6)

A reaction was carried out in a manner similar to the Example 68-(6)using Compound 6 (400 mg) to obtain Compound 8 (429 mg) as a colorlessviscous material.

MS (m/z): 590/592 [M+H]⁺

(7)

A reaction was carried out in a manner similar to the Example 68-(7)using Compound 8 (242 mg) to obtain Compound 9 (210 mg) as a colorlesssolid.

MS (m/z): 576/578 [M+H]⁺

(8)

To a solution of Compound 9 (205 mg) in tetrahydrofuran (4 mL) was addeda 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.78mL), and the mixture was stirred at 70° C. for 23 hours. A saturatedaqueous ammonia chloride solution was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (chloroform:methanol=100/0 to 90/10) to obtain amixture of Compounds 9 and 10. To this were added 2 mL oftrifluoroacetic acid and 0.2 mL of water, and the mixture was stirred atroom temperature for 2 hours. After the reaction solution was ice cooledand neutralized with a 1N aqueous sodium hydroxide solution, its pH wasadjusted to 4 with 1N hydrochloric acid, and then it was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (chloroform:methanol=100/0 to 90/10) to obtain Compound10 (109 mg) as a colorless solid.

MS (m/z): 446/448 [M+H]⁺

Example 86

(1)

Starting from Compound 1 (4400 mg), a treatment was carried out in amanner similar to the Example 68-(6) to obtain Compound 3 (4750 mg) as apale yellow solid.

MS (m/z): 386 [M+H]⁺

(2)

To a solution of Compound 3 (4740 mg) in methylene chloride (20 mL) wasadded trifluoroacetic acid (20 mL), and the mixture was stirred at roomtemperature for 4 hours. The solvent was distilled off under reducedpressure, and azeotroped with toluene. To the residue was added diethylether, and the mixture was stirred. The obtained crystals were collectedby filtration and subsequently vacuum-dried to obtain Compound 4 (3144mg) as a colorless solid.

MS (m/z): 330 [M+H]⁺

(3)

To a solution of Compound 4 (200 mg) in methylene chloride (8 mL) wasadded N,N-dimethylformamide (7 μL), thionyl chloride (266 μL) was addeddropwise, and the mixture was stirred at room temperature for 2 hours.The solvent was distilled off under reduced pressure, and azeotroped todry with toluene. To the residue were added toluene (8 mL) and potassiumthiocyanate (354 mg), and the mixture was stirred at room temperaturefor 1 hour. After the supernatant (4 mL) was removed, to the solutioncontaining the residual insoluble salt was added methanol (0.4 mL), thetemperature was brought to 70° C., and the mixture was stirred for 2hours. After the reaction solution was cooled to room temperature, tothis was added hydrazine.monohydrate (59 μL), and the mixture wasstirred at room temperature for 1 hour. Ethyl acetate and saturatedbrine were added, and the mixture was stirred to carry out a separation.The organic layer was passed through the phase separator andsubsequently concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=70:30 to 40:60) to obtain Compound 5 (29.4 mg) as a white solid.

MS (m/z): 383 [M+H]⁺

(4)

Starting from Compound 5 (29.0 mg), a treatment was carried out in amanner similar to the Example 61-(5) to obtain Compound 6 (21.8 mg) as acolorless solid.

MS (m/z): 369 [M+H]⁺

Example 87

(1)

Starting from Compound 1 (300 mg) and Compound 2 (309 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (294 mg) as a colorless viscous material.

MS (m/z): 627 [M+H]⁺

(2)

To Compound 3 (293 mg) were added trifluoroacetic acid (1 mL) and water(0.05 mL), and the mixture was stirred at room temperature for 3 hours.The reaction solution was neutralized by addition of a 2N aqueous sodiumhydroxide solution, and stirred at room temperature for 1 hour.Subsequently, ethyl acetate was added to carry out a liquid separation.The organic layer was separated, washed with saturated brine, passedthrough the phase separator and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=60:40 to 20:80). The solvent of the fractionincluding the target compound was distilled off under reduced pressure,to the residue were added diisopropyl ether and a small amount of ethylacetate, and the obtained crystals were collected by filtration andvacuum-dried to obtain Compound 4 (147 mg) as a colorless solid.

MS (m/z): 441 [M+H]⁺

Example 88

(1)

To a solution of Compound 1 (10.0 g) in tetrahydrofuran (50 mL) wasadded N, N-dimethylformamide (0.5 mL) and thionyl chloride (12.4 mL) wasadded dropwise, and the mixture was stirred at 50° C. for 2 hours. Afterthe solvent was distilled off under reduced pressure, the residue wasdissolved in tetrahydrofuran (25 mL), and the solution was added slowlydropwise to a suspension of Compound 2 (3.87 g) in pyridine (50 mL)under ice cooling. The mixture was stirred at the same temperature for30 minutes and at room temperature for 3 hours. After the solvent wasdistilled off under reduced pressure, water (50 mL) and a 2N aqueoussodium hydroxide solution (200 mL) were added, and the mixture wasstirred at 110° C. for 3 hours. The mixture was neutralized by slowaddition of concentrated hydrochloric acid (about 40 mL) under icecooling, and the obtained crystals were collected by filtration. Thecrystals were washed with diethyl ether and vacuum-dried to obtainCompound 3 (8.36 g) as a pale yellow solid.

MS (m/z): 290/292 [M+H]⁺

(2)

To a suspension of Compound 3 (8.20 g) in ethanol (19 mL) was addeddropwise a 2N aqueous sodium hydroxide solution (15.5 mL) and methyliodide (1.93 mL) was further added, and the mixture was stirred at roomtemperature for 5 minutes. The obtained crystals were collected byfiltration, washed with water and diethyl ether, and subsequently driedto obtain Compound 4 (3.95 g) as a pale yellowish brown solid.

MS (m/z): 304/306 [M+H]⁺

(3)

Starting from Compound 4 (3940 mg), a treatment was carried out in amanner similar to the Example 61-(3) to obtain Compound 5a (1353 mg) andCompound 5b (1020 mg) as colorless viscous materials respectively.

Compound 5a: MS (m/z): 434/436 [M+H]⁺

Compound 5b: MS (m/z): 434/436 [M+H]⁺

(4)

Starting from Compound 5a (1330 mg), a treatment was carried out in amanner similar to the Example 68-(4) to obtain Compound 6a (1221 mg) asa pale yellow viscous material.

MS (m/z): 466/468 [M+H]⁺

(5)

Starting from Compound 6a (800 mg) and Compound 7 (261 μL), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 8a (481 mg) as a colorless viscous material.

MS (m/z): 446/448 [M+H]⁺

(6)

Starting from Compound 8a (479 mg) and Compound 9 (393 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 10a (538 mg) as a colorless viscous material.

MS (m/z): 589/591 [M+H]⁺

(7)

To Compound 10a (300 mg) in tetrahydrofuran (4 mL) was added dropwise a1M tetrabutylammonium fluoride in tetrahydrofuran (2.5 mL), and themixture was stirred at 70° C. for 4 days. After neutralization byaddition of 1N aqueous hydrochloric acid solution, an extraction withethyl acetate was carried out. The organic layer was washed withsaturated brine, passed through the phase separator and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=65:35 to 5:95) to obtainCompound 11 (136 mg) as a colorless solid.

MS (m/z): 445/447 [M+H]⁺

Example 89

(1)

Starting from Compound 1 (400 mg) and Compound 2 (209 mg), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 3 (368 mg) as a pale yellow viscous material.

MS (m/z): 646 [M+H]⁺

(2)

Starting from Compound 3 (366 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (218 mg) as acolorless solid.

MS (m/z): 502 [M+H]⁺

Example 90

(1)

Starting from Compound 1 (300 mg), a treatment was carried out in amanner similar to the Example 69-(2) to obtain Compound 3 (257 mg) as acolorless viscous material.

MS (m/z): 608 [M+H]⁺

(2)

Starting from Compound 3 (255 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (150 mg) as acolorless solid.

MS (m/z): 464 [M+H]⁺

Example 91

(1)

Starting from Compound 1 (260 mg) and Compound 2 (304 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (279 mg) as a pale yellow viscous material.

MS (m/z): 610 [M+H]⁺

(2)

Starting from Compound 3 (278 mg), a treatment was carried out in amanner similar to the Example 87-(2) to obtain Compound 4 (83.4 mg) as acolorless solid.

MS (m/z): 424 [M+H]⁺

Example 92

(1)

Starting from Compound 1 (330 mg) and Compound 2 (473 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (511 mg) as a pale brown viscous material.

MS (m/z): 630 [M+H]⁺+

(2)

Starting from Compound 3 (508 mg), a treatment was carried out in amanner similar to the Example 88-(7) to obtain Compound 4 (217 mg) as acolorless solid.

MS (m/z): 410 [M+H]⁺

Example 93

(1)

Starting from Compound 1 (380 mg) and Compound 2 (523 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (432 mg) as a colorless viscous material.

MS (m/z): 647 [M+H]⁺

(2)

Starting from Compound 3 (428 mg), a treatment was carried out in amanner similar to the Example 88-(7) to obtain Compound 4 (204 mg) as acolorless solid.

MS (m/z): 427 [M+H]⁺

Example 94

(1)

Starting from Compound 1 (200 mg) and Compound 2 (104 mg), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 3 (85.2 mg) as a colorless viscous material.

MS (m/z): 584 [M+H]⁺

(2)

Starting from Compound 3 (85.0 mg), a treatment was carried out in amanner similar to the Example 88-(7) to obtain Compound 4 (36.5 mg) as acolorless solid.

MS (m/z): 440 [M+H]⁺

Example 95

(1)

Starting from Compound 1 (400 mg) and Compound 2 (99 μL), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 3 (385 mg) as a pale yellow viscous material.

MS (m/z): 596 [M+H]⁺

(2)

Starting from Compound 3 (338 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (252 mg) as acolorless solid.

MS (m/z): 452 [M+H]⁺

Example 96

(1)

Starting from Compound 1 (230 mg) and Compound 2 (302 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (274 mg) as a colorless viscous material.

MS (m/z): 610 [M+H]⁺

(2)

Starting from Compound 3 (273 mg), a treatment was carried out in amanner similar to the Example 87-(2) to obtain Compound 4 (109 mg) as acolorless solid.

MS (m/z): 424 [M+H]⁺

Example 97

(1)

Starting from Compound 1 (230 mg) and Compound 2 (292 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (195 mg) as a pale yellowish brown viscous material.

MS (m/z): 554 [M+H]⁺

(2)

Starting from Compound 3 (194 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (109 mg) as acolorless solid.

MS (m/z): 410 [M+H]⁺

Example 98

(1)

Starting from Compound 1 (230 mg) and Compound 2 (314 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (145 mg) as a colorless viscous material.

MS (m/z): 626 [M+H]⁺

(2)

Starting from Compound 3 (144 mg), a treatment was carried out in amanner similar to the Example 87-(2) to obtain Compound 4 (65.8 mg) as acolorless solid.

MS (m/z): 440 [M+H]⁺

Example 99

(1)

Starting from Compound 1 (1350 mg) and Compound 2 (1273 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (1610 mg) as a pale yellowish brown viscous material.

MS (m/z): 576 [M+H]⁺

(2)

Starting from Compound 3 (400 mg) and Compound 4 (209 mg), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 5 (331 mg) as a pale yellowish brown viscous material.

MS (m/z): 646 [M+H]⁺

(3)

Starting from Compound 5 (329 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 6 (208 mg) as acolorless solid.

MS (m/z): 502 [M+H]⁺

Example 100

(1)

Starting from Compound 1 (400 mg) and Compound 2 (156 mg), a treatmentwas carried out in a manner similar to the Example 69-(2) to obtainCompound 3 (260 mg) as a colorless viscous material.

MS (m/z): 608 [M+H]⁺

(2)

Starting from Compound 3 (258 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (175 mg) as acolorless solid.

MS (m/z): 464 [M+H]⁺

Example 101

(1)

Starting from Compound 1 (400 mg) and Compound 2 (99 μL), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 3 (340 mg) as a colorless solid.

MS (m/z): 596 [M+H]⁺

(2)

Starting from Compound 3 (338 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 4 (200 mg) as acolorless solid.

MS (m/z): 452 [M+H]⁺

Example 102

(1)

Starting from Compound 1 (260 mg) and Compound 2 (317 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (259 mg) as a pale yellow viscous material.

MS (m/z): 626 [M+H]⁺

(2)

Starting from Compound 3 (258 mg), a treatment was carried out in amanner similar to the Example 87-(2) to obtain Compound 4 (143 mg) as apale yellow solid.

MS (m/z): 440 [M+H]⁺

Example 103

(1)

Starting from Compound 1 (2.03 g), a treatment was carried out in amanner similar to the Example 88-(1) to obtain Compound 3 (791 mg) as ayellowish brown solid.

MS (m/z): 258/260 [M+H]⁺

(2)

Starting from Compound 3 (785 mg), a treatment was carried out in amanner similar to the Example 88-(2) to obtain Compound 4 (593 mg) as ayellowish brown solid.

MS (m/z): 272/274 [M+H]⁺

(3)

Starting from Compound 4 (560 mg), a treatment was carried out in amanner similar to the Example 61-(3) to obtain Compound 5a (131 mg) andCompound 5b (369 mg) as a colorless solid and a pale yellow solidrespectively.

Compound 5a: MS (m/z): 402/404 [M+H]⁺

Compound 5b: MS (m/z): 402/404 [M+H]⁺

(4)

Starting from Compound 5a (127 mg), a treatment was carried out in amanner similar to the Example 79-(5) to obtain Compound 6a (110 mg) as acolorless solid.

MS (m/z): 434/436 [M+H]⁺

(5)

Starting from Compound 6a (108 mg) and Compound 7 (74.6 mg), a treatmentwas carried out in a manner similar to the Example 68-(5) to obtainCompound 8a (121 mg) as a colorless solid.

MS (m/z): 504/506 [M+H]⁺

(6)

Starting from Compound 8a (120 mg) and Compound 9 (87.3 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 10a (123 mg) as a colorless solid.

MS (m/z): 647 [M+H]⁺

(7)

Starting from Compound 10a (123 mg), a treatment was carried out in amanner similar to the Example 68-(7) to obtain Compound 11 (84.2 mg) asa pale yellow solid.

MS (m/z): 503 [M+H]⁺

Example 104

(1)

Starting from Compound 1 (3.00 g) and Compound 2 (6.03 g), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 3 (2.07 g) as a pale yellow powder.

MS (m/z): 329 [M+H]⁺

(2)

Starting from Compound 3 (2060 mg), a treatment was carried out in amanner similar to the Example 68-(1) to obtain Compound 4 (853 mg) as apale yellow solid.

MS (m/z): 433 [M+H]⁺

(3)

Starting from Compound 4 (850 mg), a treatment was carried out in amanner similar to the Example 68-(2) to obtain Compound 5 (480 mg) as acolorless solid.

MS (m/z): 399 [M+H]⁺

(4)

Starting from Compound 5 (64.0 mg), a treatment was carried out in amanner similar to the Example 61-(5) to obtain Compound 6 (52.4 mg) as acolorless solid.

MS (m/z): 385 [M+H]⁺

Example 105

(1)

A reaction was carried out in a manner similar to the Example 53-(1)using a mixture of Compounds 1a and 1b (200 mg) and Compound 2 (216 mg)to obtain a mixture of Compounds 3a and 3b (243 mg) as a pale yellowsolid.

MS (m/z): 526 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 53-(2)using the mixture of Compounds 3a and 3b (240 mg) to obtain a mixture ofCompounds 4a and 4b (245 mg) as a pale yellow oil.

MS (m/z): 436 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 55-(1)using the mixture of Compounds 4a and 4b (140 mg) and Compound 5 (140mg) to obtain a mixture of Compounds 6a and 6b (111 mg) as a pale yellowoil. A reaction was carried out in a manner similar to the Example51-(5) using the mixture of Compounds 6a and 6b (110 mg) to obtainCompound 7 (17 mg) as a white solid.

MS (m/z): 406 [M+H]⁺

Example 106

(1)

A reaction was carried out in a manner similar to the Example 55-(1)using a mixture of Compounds 1a and 1b (150 mg) and Compound 2 (120 mg)to obtain a mixture of Compounds 3a and 3b (140 mg) as a colorlesssolid.

MS (m/z): 593 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 51-(5)using the mixture of Compounds 3a and 3b (140 mg) to obtain Compound 4(39 mg) as a colorless solid.

MS (m/z): 407 [M+H]⁺

Example 107

(1)

A mixture of Compound 1 (1.02 g), Compound 2 (1.10 g), copper(I) bromide(40 mg), cesium carbonate (5.45 g) and dimethylsulfoxide (20 mL) wasstirred at 100° C. for 16 hours. To the reaction solution were added 1Nhydrochloric acid and ethyl acetate, and the insoluble matter wasremoved by celite-filtration. The filtrate was extracted with ethylacetate, and the extract was washed with water and saturated brine. Theextract was dried over anhydrous magnesium sulfate and concentrated, andthe residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 70:30) to obtain Compound 3 (721 mg) asa colorless solid.

MS (m/z): 293/295 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 50-(5)using Compound 3 (715 mg) to obtain Compound 4a (827 mg) and Compound 4b(144 mg) as colorless oils.

MS (m/z): 423/425 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 50-(6)using Compound 4a (285 mg) and Compound 5 (362 mg) to obtain Compound 6a(294 mg) as a pale yellow viscous material.

MS (m/z): 552 [M+H]⁺

(4)

A reaction was carried out in a manner similar to the Example 52-(7)using Compound 6a (287 mg) to obtain Compound 7 (251 mg) as a paleyellow viscous material.

MS (m/z): 538 [M+H]⁺

(5)

A reaction was carried out in a manner similar to the Example 52-(8)using Compound 7 (243 mg) to obtain Compound 8 (114 mg) as a colorlesspowder.

MS (m/z): 408 [M+H]⁺

Example 108

(1)

A solution of Compound 1 (5 g), EDC hydrochloride (7.46 g) and HOBt(5.26 g) in N,N-dimethylformamide (50 mL) was stirred at roomtemperature for 2 hours. This solution was added dropwise to a solutionof hydrazine hydrate (3.16 mL) in acetonitrile (50 mL) at 0° C., and themixture was stirred at the same temperature for 1 hour and further atroom temperature for 30 minutes. The deposit was removed by filtration,and a saturated aqueous sodium hydrogen carbonate solution and ethylacetate were added to the filtrate, and the mixture was extracted. Theextract was washed with saturated brine and dried over anhydrous sodiumsulfate, and the solvent was distilled off. To the residue were added 4Nhydrogen chloride/dioxane (3 mL) and diethyl ether, and the mixture wasstirred. The deposit was filtered and vacuum-dried to obtain Compound 2(1335 mg) as a colorless powder.

MS (m/z): 169 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 50-(6)using Compound 3 (4 g) and Compound 4 (7.37 g) to obtain Compound 5(6.26 g) as a colorless solid.

MS (m/z): 311 [M+H]⁺

(3)

A mixture of Compound 5 (6.24 g), a 50% aqueous hydroxyamine solution(26.6 g), methanol (45 mL) and tetrahydrofuran (45 mL) was stirred at80° C. for 2 hours. After the solvent was distilled off, chloroform andwater were added and the mixture was extracted. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off and vacuum-dried to obtain Compound 6 (6.93 g)as a colorless solid.

MS (m/z): 344 [M+H]⁺

(4)

To a solution of Compound 6 (6.92 g) in acetic acid (20 mL) was addedacetic anhydride (3.34 mL), and the mixture was stirred at roomtemperature for 2 hours. The solvent was distilled off, the residue wasdissolved in methanol (100 mL), 10% palladium-carbon was added under anitrogen stream, and the mixture was stirred under a hydrogen atmosphereat room temperature for 6 hours. The catalyst was filtered off by amembrane-filter, the solvent was distilled off, and subsequently diethylether was added. The deposit was collected by filtration andvacuum-dried to obtain Compound 7 (6.71 g) as a pale yellow solid.

MS (m/z): 328 [M+H]⁺

(5)

A mixture of Compound 7 (400 mg), Compound 2 (211 mg), sodium methylate(167 mg) and ethanol (6 mL) was stirred at 100° C. for 17 hours. Thetemperature of the reaction solution was brought to room temperature,and ethyl acetate, 1N hydrochloric acid and water were added, and thereaction solution was extracted. After the extract was washed withsaturated brine and passed through the phase separator, the solvent wasdistilled off. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=70:30 to 45:55) to obtainCompound 8 (276 mg) as a colorless oil.

MS (m/z): 461 [M+H]⁺

(6)

A reaction was carried out in a manner similar to the Example 50-(8)using Compound 8 (275 mg) to obtain Compound 9 (262 mg) as a colorlesssolid.

MS (m/z): 447 [M+H]⁺

Example 109

(1)

A mixture of Compound 1 (400 mg), Compound 2 (127 mg), sodium methylate(112 mg), ammonium chloride (55 mg) and N,N-dimethylformamide (6 mL) wasstirred at 100° C. for 25 hours. The reaction solution was cooled toroom temperature, and ethyl acetate, a saturated aqueous ammoniumchloride solution and water were added, and the mixture was extracted.After the extract was washed with saturated brine and passed through thephase separator, the solvent was distilled off. The residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=70:30 to45:55) to obtain Compound 3 (112 mg) as a pale yellow viscous material.

MS (m/z): 395 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 50-(8)using Compound 3 (112 mg) to obtain Compound 4 (72 mg) as a pale yellowsolid.

MS (m/z): 381 [M+H]⁺

Example 110

(1)

A reaction was carried out in a manner similar to the Example 109-(1)using Compound 1 (200 mg) and Compound 2 (103 mg) to obtain Compound 3(65 mg) as a pale yellow viscous material.

MS (m/z): 459 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 50-(8)using Compound 3 (180 mg) to obtain Compound 4 (145 mg) as a colorlesssolid.

MS (m/z): 445 [M+H]⁺

Example 111

(1)

A reaction was carried out in a manner similar to the Example 109-(1)using Compound 1 (400 mg) and Compound 2 (180 mg) to obtain Compound 3(234 mg) as a pale yellow viscous material.

MS (m/z): 409 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 50-(8)using Compound 3 (218 mg) to obtain Compound 4 (149 mg) as a colorlesssolid.

MS (m/z): 395 [M+H]⁺

Example 112

(1)

A reaction was carried out in a manner similar to the Example 50-(6)using Compound 1 (297 mg) and Compound 2 (300 mg) to obtain Compound 3(292 mg) as a colorless viscous material.

MS (m/z): 566 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 52-(7)using Compound 3 (288 mg) to obtain Compound 4 (305 mg) as a colorlessviscous material.

MS (m/z): 552 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 52-(8)using Compound 4 (280 mg) to obtain Compound 5 (149 mg) as a colorlesssolid.

MS (m/z): 422 [M+H]⁺

Example 113

(1)

A reaction was carried out in a manner similar to the Example 85-(1)using Compound 1 (5.3 g) to obtain Compound 2 (4.05 g) as a beige solid.

MS (m/z): 275/277 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 85-(2)using Compound 2 (4.03 g) to obtain Compound 3 (3.13 g) as a yellowsolid.

MS (m/z): 289/291 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 50-(5)using Compound 3 (3.1 g) to obtain Compound 4a (2.55 g) as a colorlessviscous material and Compound 4b (1.70 g) as a colorless solid.

4a: MS (m/z): 419/421 [M+H]⁺

4b: MS (m/z): 419/421 [M+H]⁺

(4)

A reaction was carried out in a manner similar to the Example 68-(4)using Compound 4b (1.62 g) to obtain Compound 5 (1.355 g) as a colorlesssolid.

MS (m/z): 451/453 [M+H]⁺

(5)

A reaction was carried out in a manner similar to the Example 50-(6)using Compound 5 (300 mg) and Compound 6 (255 mg) to obtain Compound 7(347 mg) as a colorless solid.

MS (m/z): 594 [M+H]⁺

(6)

To a solution of isopropanol (77 mg) in tetrahydrofuran (3 mL) was added60% sodium hydride (35 mg) at 0° C., and the mixture was stirred for 10minutes. To this was added a solution of Compound 7 (345 mg) intetrahydrofuran (3 mL), and the mixture was stirred for 10 minutes. A 2Naqueous sodium hydroxide solution (2.9 mL) and methanol (3 mL) were thenadded, and the mixture was stirred at room temperature overnight. Thereaction solution was concentrated, the residue was neutralized with 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. After the extract was concentrated under reducedpressure, the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtainCompound 8 (279 mg) as a colorless viscous material.

MS (m/z): 560 [M+H]⁺

(7)

A reaction was carried out in a manner similar to the Example 88-(7)using Compound 8 (278 mg) to obtain Compound 9 (60 mg) as a colorlesssolid.

MS (m/z): 430 [M+H]⁺

Example 114

(1)

Starting from Compound 1 (389 mg) and 3-pentanol (120 mg), a reactionwas carried out in a manner similar to the Example 113-(6) to obtainCompound 2 (292 mg) as a colorless viscous material.

MS (m/z): 570 [M+H]⁺

(2)

Starting from Compound 2 (290 mg), a reaction was carried out in amanner similar to the Example 88-(7) to obtain Compound 3 (60 mg) as acolorless solid.

MS (m/z): 439 [M+H]⁺

Example 115

(1)

A mixture of Compound 1 (230 mg), potassium ferrocyanide (II)tetrahydrate (66 mg), palladium acetate (9 mg), butyldi-1-adamantylphosphine (42 mg), sodium carbonate (17 mg) andN-methylpyrrolidone (5 mL) was stirred under a nitrogen atmosphere at160° C. for 18 hours. To the reaction solution was added water, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate. After theextract was concentrated under reduced pressure, the obtained residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=100:0 to 80:20) to obtain Compound 2 (24 mg) as a colorlessviscous material.

MS (m/z): 580 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 88-(7)using Compound 2 (20 mg) to obtain Compound 3 (11 mg) as a colorlesssolid.

MS (m/z): 436 [M+H]⁺

Example 116

(1)

Starting from Compound 1 (300 mg) and cyclobutanol (75 mg), the reactionwas carried out in a manner similar to the Example 113-(6) to obtainCompound 2 (270 mg) as a colorless powder.

MS (m/z): 554 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 88-(7)using Compound 2 (270 mg) to obtain Compound 3 (110 mg) as a colorlesssolid.

MS (m/z): 424 [M+H]⁺

Example 117

(1)

A reaction was carried out in a manner similar to the Example 51-(2)using Compound 1 (2.15 g) and Compound 2 (2.8 g) to obtain Compound 3(2.82 g) as a pale pink solid.

MS (m/z): 314/316 [M+H]⁺

(2)

A mixture of Compound 3 (2.81 g), Compound 4 (2.73 g),bis(triphenylphosphine)palladium(II) chloride (190 mg), potassiumacetate (2.63 g) and dioxane (56 mL) was stirred under a nitrogenatmosphere at 100° C. for 4 hours. The reaction solution was filteredthrough Celite, and the mixture was washed with ethyl acetate. Thefiltrate was washed with saturated brine, and dried over anhydrousmagnesium sulfate. After the filtrate was concentrated under reducedpressure, the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtainCompound 5 (1.384 g) as a colorless solid.

MS (m/z): 362 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 50-(6)using Compound 5 (392 mg) and Compound 6 (400 mg) to obtain Compound 7(383 mg) as a colorless viscous material.

MS (m/z): 588 [M+H]⁺

(4)

A reaction was carried out in a manner similar to the Example 113-(6)using Compound 7 (380 mg) and cyclobutanol (93 mg) to obtain Compound 8(293 mg) as a colorless solid.

MS (m/z): 566 [M+H]⁺

(5)

Starting from Compound 8 (290 mg), the reaction was carried out in amanner similar to the Example 88-(7) to obtain Compound 9 (190 mg) as acolorless solid.

MS (m/z): 436 [M+H]⁺

Example 118

(1)

A reaction was carried out in a manner similar to the Example 113-(6)using Compound 1 (300 mg) and cyclobutanol (56 mg) to obtain Compound 2(305 mg) as a colorless viscous material.

MS (m/z): 554 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 88-(7)using Compound 2 (304 mg) to obtain Compound 3 (142 mg) as a colorlesssolid.

MS (m/z): 424 [M+H]⁺

Example 119

(1)

A reaction was carried out in a manner similar to the Example 50-(6)using Compound 1 (367 mg) and Compound 2 (400 mg) to obtain Compound 3(515 mg) as a colorless viscous material.

MS (m/z): 588 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 113-(6)using Compound 3 (513 mg) and cyclobutanol (126 mg) to obtain Compound 4(463 mg) as a colorless solid.

MS (m/z): 566 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 88-(7)using Compound 4 (460 mg) to obtain Compound 5 (286 mg) as a colorlesssolid.

MS (m/z): 436 [M+H]⁺

Example 120

(1)

Starting from Compound 1 (290 mg) and 2-methyl-1-propanol (56 mg), thereaction was carried out in a manner similar to the Example 113-(6) toobtain Compound 2 (199 mg) as a colorless viscous material.

MS (m/z): 556 [M+H]⁺

(2)

Starting from Compound 2 (198 mg), the reaction was carried out in amanner similar to the Example 88-(7) to obtain Compound 3 (74 mg) as acolorless solid.

MS (m/z): 426 [M+H]⁺

Example 121

(1)

A reaction was carried out in a manner similar to the Example 113-(6)using Compound 1 (290 mg) and cyclopropylmethanol (54 mg) to obtainCompound 2 (287 mg) as a colorless viscous material.

MS (m/z): 554 [M+H]⁺

(2)

Starting from Compound 2 (286 mg), the reaction was carried out in amanner similar to the Example 88-(7) to obtain Compound 3 (61 mg) as acolorless solid.

MS (m/z): 424 [M+H]⁺

Example 122

(1)

A treatment was carried out in a manner similar to the Example 113-(6)using Compound 1 (290 mg) and cyclobutylmethanol (65 mg) to obtainCompound 2 (279 mg) as a colorless viscous material.

MS (m/z): 568 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 88-(7)using Compound 2 (278 mg) to obtain Compound 3 (107 mg) as a colorlesssolid.

MS (m/z): 438 [M+H]⁺

Example 123

(1)

Starting from Compound 1 (350 mg) and 2-methyl-1-propanol (90 mg), thereaction was carried out in a manner similar to the Example 113-(6) toobtain Compound 2 (319 mg) as a colorless viscous material.

MS (m/z): 556 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 88-(7)using Compound 2 (317 mg) to obtain Compound 3 (111 mg) as a colorlesssolid.

MS (m/z): 426 [M+H]⁺

Example 124

(1)

A reaction was carried out in a manner similar to the Example 113-(6)using Compound 1 (350 mg) and cyclopropylmethanol (88 mg) to obtainCompound 2 (345 mg) as a colorless viscous material.

MS (m/z): 554 [M+H]⁺

(2)

Starting from Compound 2 (343 mg), a reaction was carried out in amanner similar to the Example 88-(7) to obtain Compound 3 (129 mg) as acolorless solid.

MS (m/z): 424 [M+H]⁺

Example 125

(1)

A reaction was carried out in a manner similar to the Example 113-(6)using Compound 1 (350 mg) and cyclobutylmethanol (209 mg) to obtainCompound 2 (345 mg) as a colorless viscous material.

MS (m/z): 568 [M+H]⁺

(2)

Starting from Compound 2 (343 mg), a reaction was carried out in amanner similar to the Example 88-(7) to obtain Compound 3 (115 mg) as acolorless solid.

MS (m/z): 438 [M+H]⁺

Example 126

(1)

Starting from Compound 1 (300 mg) and cyclopentanol (119 mg), a reactionwas carried out in a manner similar to the Example 68-(5) to obtainCompound 2 (300 mg) as a colorless solid.

MS (m/z): 439/441 [M+H]⁺

(2)

A reaction was carried out in a manner similar to the Example 68-(6)using Compound 2 (298 mg) and Compound 3 (261 mg) to obtain Compound 4(359 mg) as a colorless viscous material.

MS (m/z): 582 [M+H]⁺

(3)

A reaction was carried out in a manner similar to the Example 88-(7)using Compound 2 (355 mg) to obtain Compound 4 (178 mg) as a colorlesssolid.

MS (m/z): 438 [M+H]⁺

Example 127

(1)

A treatment was carried out in a manner similar to the Example 68-(5)using Compound 1 (400 mg) and cyclopentanol (177 mg) to obtain Compound2 (332 mg) as a colorless viscous material.

MS (m/z): 395/397 [M+H]⁺

(2)

Starting from Compound 2 (330 mg) and Compound 3 (350 mg), a treatmentwas carried out in a manner similar to the Example 68-(6) to obtainCompound 4 (304 mg) as a colorless viscous material.

MS (m/z): 582 [M+H]⁺

(3)

A treatment was carried out in a manner similar to the Example 88-(7)using Compound 4 (303 mg) to obtain Compound 5 (139 mg) as a colorlesssolid.

MS (m/z): 438 [M+H]⁺

Reference Example 1

Compound 1 (2′-(trifluoromethoxy)acetophenone) (1.00 g),N-bromosuccinimide (0.87 g) and toluene sulfonic acid monohydrate (84mg) were stirred at room temperature overnight. Dichloromethane andsaturated brine were added to the reaction solution to carry out aliquid separation. The organic layer was separated and dried overanhydrous sodium sulfate, and subsequently the solvent was distilled offunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=99:1 to 94:6) to obtainCompound 2 (1.14 g).

NMR (400 MHz, DMSO-d₆): 7.97 (1H, dd, J=8.0, 4.0 Hz), 7.75 (1H, m), 7.57(1H, t, J=8.0 Hz), 7.53 (1H, d, J=8.0 Hz), 4.85 (1H, s)

Reference Example 2

(1) Compound 1 (2′-hydroxyacetophenone) (1.20 mL), 2-bromoethyl methylether (1.88 mL) and cesium carbonate (3.26 g) were dissolved inN,N-dimethylformamide (10 mL), and the mixture was stirred at 90° C.overnight. After the temperature of the reaction solution was broughtback to room temperature, ethyl acetate and water were added to carryout a liquid separation. The organic layer was separated, washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=95:5 to 80:20) to obtain Compound 2 (1.75 g).

MS (m/z): 195 [M+H]⁺

(2) A treatment was carried out in a manner similar to Reference Example1 using Compound 2 (1.74 g) to obtain Compound 3 (2.24 g).

MS (m/z): 273/275 [M+H]⁺

Reference Example 3

(1) Compound 1 (2′-hydroxyacetophenone) (0.60 mL) was dissolved indimethylsulfoxide (25 mL), 2-iodopropane (1.70 g) and potassiumphosphate (2.12 g) were added, and the mixture was stirred at 60° C. for4 hours. After the temperature of the reaction solution was brought backto room temperature, ethyl acetate and water were added to carry out aliquid separation. The organic layer was separated, washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=98:2 to 92:8) to obtain Compound 2 (0.74 g).

MS (m/z): 179 [M+H]⁺

(2) Compound 2 (200 mg) was dissolved in ethyl acetate (2.5 mL) andchloroform (2.5 mL), copper bromide (0.50 g) was added, and the mixturewas heated at reflux under a nitrogen atmosphere for 4 hours. After thetemperature of the reaction solution was brought back to roomtemperature, the reaction solution was filtered through Celite andwashed with ethyl acetate. The filtrate was concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=98:2 to 92:8) to obtain Compound3 (267 mg).

MS (m/z): 257/259 [M+H]⁺

Reference Example 4

Compound 1 (2′-fluoro-6′-(trifluoromethyl)acetophenone) (500 mg) wasdissolved in tetrahydrofuran (10 mL), benzyltrimethylammonium tribromide(1.04 g) was added, and the mixture was stirred at room temperature for2 hours. The reaction solution was concentrated under reduced pressure,to the residue was added diethyl ether, and the obtained solid wasfiltered and washed by diethyl ether. The filtrate was concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=99:1 to 95:5) toobtain Compound 2 (632 mg).

NMR (400 MHz, DMSO-d₆): 7.77 (3H, m), 4.83 (1H, d, J=1.2 Hz)

Reference Example 5

Compound 1 (4-methoxy-2-(trifluoromethyl)benzoic acid) (0.50 g) wasdissolved in dichloromethane (10 mL), and oxalyl chloride (0.40 mL) wasadded dropwise. To this was added N,N-dimethylformamide (5 drops), andthe mixture was stirred at room temperature for 1 hour. After thereaction solution was concentrated under reduced pressure, acetonitrile(10 mL) was added. A 2M trimethylsilyldiazomethane-n-hexane solution(2.4 mL) was added dropwise under ice cooling, and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasice-cooled, a 48% hydrobromic acid (0.39 mL) was added dropwise, and themixture was stirred for 1 hour. Ethyl acetate and a saturated aqueoussodium hydrogen carbonate solution were added to the reaction solutionto carry out a liquid separation. The organic layer was separated anddried over anhydrous sodium sulfate, and subsequently the solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=98:2 to92:8) to obtain Compound 2 (0.44 g).

MS (m/z): 297/299 [M+H]⁺

Reference Example 6

(1) Compound 1 (3-acetylbenzoic acid) (500 mg) was dissolved inN,N-dimethylformamide (10 mL), potassium carbonate (421 mg) and benzylbromide (362 μL) were added, and the mixture was stirred at roomtemperature overnight. Ethyl acetate and water were added to thereaction solution to carry out a liquid separation, the organic layerwas dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The obtained residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=99:1 to 85:15) toobtain Compound 2 (763 mg).

MS (m/z): 272 [M+NH₄]⁺

(2) A treatment was carried out in a manner similar to Reference Example1 using Compound 2 (760 mg) to obtain Compound 3 (668 mg).

MS (m/z): 333/335 [M+H]⁺

Reference Example 7-1

(1) Compound 1 (4-bromophenol) (61.0 g), Compound 2 (methylhydroxypivalate) (69.9 g) and triphenylphosphine (138.7 g) weredissolved in tetrahydrofuran (350 mL), and the mixture was cooled to 0°C. under a nitrogen atmosphere. Subsequently, a 40% diethylazodicarboxylate-toluene solution (240 mL) was added dropwise, and themixture was stirred while the temperature was brought back to roomtemperature and then at 80° C. overnight. After the temperature of thereaction solution was brought back to room temperature, the reactionsolution was concentrated under reduced pressure, to the obtainedresidue was added diethyl ether (500 mL), and the obtained solid wasfiltered and washed with diethyl ether. The filtrate was concentratedunder reduced pressure and the obtained residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=100:0, 19:1 and to9:1) to obtain Compound 3 (102.2 g).

MS (m/z): 304/306 [M+NH₄]⁺

(2) Compound 3 (102.2 g), bis(pinacolato)diboron (98.5 g),[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (7.73 g),1,1′-bis(diphenylphosphino)ferrocene (5.86 g), and potassium acetate(103.8 g) were added to 1,4-dioxane (470 mL), and the mixture wasstirred under a nitrogen atmosphere at 80° C. overnight. After thetemperature of the reaction solution was brought back to roomtemperature, the reaction solution was concentrated under reducedpressure, and ethyl acetate and water were added to the obtained residueto carry out a liquid separation. The organic layer was separated,washed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=100:0, 9:1 and to 4:1), to the obtained residue was addedn-hexane, and the mixture was stirred under ice-cooling for 1 hour. Theobtained solid was collected by filtration and dried to obtain Compound4 (95.5 g).

MS (m/z): 335 [M+H]⁺

(3) Compound 4 (87.6 g) and Compound 5 (2-chloro-5-cyanopyridine) (40.0g) were dissolved in dimethoxyethane (550 mL), and a 2M aqueous sodiumcarbonate solution (525 mL) was added. To this was addedtetrakis(triphenylphosphine)palladium (21.2 g) under a nitrogenatmosphere, and the mixture was stirred at 90° C. overnight. After thetemperature of the reaction solution was brought back to roomtemperature, ethyl acetate and water were added to carry out a liquidseparation. The organic layer was separated, washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=9:1, 4:1 andto 2:1) to obtain Compound 6 (77.4 g).

MS (m/z): 311 [M+H]⁺

(4) Compound 6 (6.27 g) was dissolved in tetrahydrofuran (100 mL) andmethanol (100 mL), a 50% aqueous hydroxylamine solution (40 mL) wasadded, and the mixture was stirred at 80° C. for 4 hours. After thetemperature of the reaction solution was brought back to roomtemperature, the reaction solution was concentrated under reducedpressure, and chloroform and water were added to the obtained residue tocarry out a liquid separation. The organic layer was separated, washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain Compound 7(6.70 g).

MS (m/z): 344 [M+H]⁺

(5) Compound 7 (6.68 g) was dissolved in acetic acid (60 mL), aceticanhydride (4 mL) was added, and the mixture was stirred at roomtemperature for 1.75 hours. After the reaction solution was concentratedunder reduced pressure, to the obtained residue were addedtetrahydrofuran (70 mL) and methanol (300 mL), 10% palladium/carbon(1.25 g) was added under a nitrogen atmosphere, and the mixture wassubjected to hydrogen substitution, and stirred at room temperature for2 hours. The reaction solution was filtered, and the residue was washedwith methanol. After the filtrate was concentrated under reducedpressure, ethyl acetate was added to the residue, and the obtaineddeposit was washed with ethyl acetate and dried to obtain Compound 8(6.81 g) as an acetate salt.

MS (m/z): 328 [M+H]⁺

Reference Examples 7-2 to 7-19

A treatment was carried out in a manner similar to Reference Example 7-1to obtain compounds of Reference Examples 7-2 to 7-19 in Table 27 below.

TABLE 27 Reference Example Intermediate 1 Intermediate 2 7-2 

7-3 

7-4 

7-5 

7-6 

7-7 

7-8 

7-9 

7-10

7-11

7-12

7-13

7-14

7-15

7-16

7-17

7-18

7-19

Reference Example Product MS (m/z) 7-2 

328 [M + H]⁺ 7-3 

342 [M + H]⁺ 7-4 

342 [M + H]⁺ 7-5 

356 [M + H]⁺ 7-6 

343 [M + H]⁺ 7-7 

344 [M + H]⁺ 7-8 

403 [M + H]⁺ 7-9 

330 [M + H]⁺ 7-10

360 [M + H]⁺ 7-11

398 [M + H]⁺ 7-12

341 [M + H]⁺ 7-13

415 [M + H]⁺ 7-14

414 [M + H]⁺ 7-15

397 [M + H]⁺ 7-16

384 [M + H]⁺ 7-17

400 [M + H]⁺ 7-18

356 [M + H]⁺ 7-19

342 [M + H]⁺

Reference Example 8

Compound 1 (4.9 g) and Compound 2 (5 g) were dissolved inN,N-dimethylformamide (50 mL), and a 60% sodium hydride (1.16 g) wasadded portionwise under ice cooling. The temperature of the reactionsolution was elevated to room temperature, and the reaction solution wasstirred for 4 hours. After a saturated aqueous ammonium chloridesolution was added under ice cooling, ethyl acetate and water were addedto carry out a liquid separation. The organic layer was separated,washed with water, and dried over sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=100:0 to97:3) to obtain Compound 3 (6.71 g).

MS (m/z): 356/358 [M+H]⁺

Reference Example 9-1

Compound 1 (1.46 g), Compound 2 (1.46 g), adichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(PdCl₂(dppf))-methylene chloride complex (399 mg) and a 2N aqueouscesium carbonate solution (7.33 mL) were added to 1,4-dioxane (29 mL),and the mixture was stirred at 100° C. for 5 hours. The reactionsolution was filtered, and ethyl acetate and water were added to thefiltrate to carry out a liquid separation. The organic layer wasseparated, washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=95:5 to 80:20) and solidified by n-hexane toobtain Compound 3 (1.39 g).

MS (m/z): 367 [M+H]⁺

Reference Examples 9-2 to 9-3

A treatment was carried out in a manner similar to Reference Example 9-1to obtain compounds of Reference Examples 9-2 and 9-3 in Table 28 below.

TABLE 28 Reference Example Intermediate 1 Intermediate 2 Product MS(m/z) 9-2

313 [M + H]⁺ 9-3

383 [M + H]⁺

Reference Example 10

(1) A treatment was carried out in a manner similar to Reference Example7-1 (4) using Compound 1 (850 mg) to obtain Compound 2 (940 mg).

MS (m/z): 392/394 [M+H]⁺

(2) Compound 2 (925 mg) was dissolved in acetic acid (9 mL) and aceticanhydride (268 μL), and the mixture was stirred at room temperature for30 minutes. Palladium chloride (46 mg) and triethyl silane (535 μL) wereadded, and the mixture was stirred at 70° C. for 4 hours. Additionaltriethyl silane (288 μL) was added, and the mixture was further stirredat the same temperature for 30 minutes. The reaction solution wasfiltered, and the filtrate was concentrated under reduced pressure.Saturated brine and ethyl acetate were added to the obtained residue tocarry out a liquid separation. The organic layer was separated, washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure. The obtained residuewas purified by NH-silica gel column chromatography(chloroform:methanol=100:0 to 90:10) and then silica gel columnchromatography (n-hexane:ethyl acetate=90:10 to 67:33) to obtainCompound 3 (201 mg).

MS (m/z): 376/378 [M+H]⁺

Reference Example 11

(1) A treatment was carried out in a manner similar to Reference Example7-1 (4) using Compound 1 (1.4 g) to obtain Compound 2 (1.51 g).

MS (m/z): 451 [M+H]⁺

(2) Compound 2 (1.32 g) was dissolved in acetic acid (30 mL) and aceticanhydride (610 μL), and the mixture was stirred at room temperature for6 hours. To the reaction solution were added methanol (10 mL) andtetrahydrofuran (10 mL), and 10% palladium-carbon (265 mg) was addedunder a nitrogen atmosphere. The reaction mixture was stirred under ahydrogen atmosphere at room temperature for 2 hours and subsequentlyfiltered through Celite, and the filtrate was concentrated under reducedpressure. To the obtained residue were added ethanol (20 mL) and a 4Nhydrogen chloride-dioxane solution (10 mL), and the mixture was stirredat room temperature overnight and further at 60° C. for 8 hours.Chloroform, methanol and an aqueous saturated sodium hydrogen carbonatesolution were added to the reaction solution to carry out a liquidseparation. The organic layer was separated, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The obtained residuewas solidified with diethyl ether to obtain Compound 3 (675 mg).

MS (m/z): 373 [M+H]⁺

Reference Example 12

(1) Compound 1 (1.86 g), Compound 2 (3.02 g) and a 28% aqueous ammonia(25 mL) were added to a mixed solvent of water (25 mL) and methanol (100mL), and the mixture was stirred at room temperature for 5 hours.Chloroform and a saturated aqueous sodium hydrogen carbonate solutionwere added to the residue obtained by concentration of the reactionsolution under reduced pressure to carry out a liquid separation. Theorganic layer was separated and dried with anhydrous sodium sulfate, andsubsequently the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=50:50 to 20:80) to obtain Compound 3 (490 mg).

MS (m/z): 300/302 [M+H]⁺

(2) To a solution of Compound 3 (475 mg) in N,N-dimethylformamide (5 mL)was added a 60% sodium hydride (95 mg) under a nitrogen atmosphere underice cooling, and the mixture was stirred at room temperature for 30minutes. To this was added 2-(trimethylsilyl)ethoxymethyl chloride (420μL) under ice cooling, and the mixture was stirred at room temperaturefor 6 hours. To the reaction solution was added a saturated aqueousammonium chloride solution, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and theaqueous layer thus obtained was extracted with ethyl acetate. Theorganic layers were combined, dried and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=87:13 to 74:26) to obtainCompound 4 (651 mg).

MS (m/z): 430/431 [M+H]⁺

Reference Example 13-1

(1) To water (15 mL) were added Compound 1(3,3-dibromo-1,1,1-trifluoropropan-2-one) (4.05 g) and sodium acetate(2.46 g), and the mixture was stirred at 95° C. for 30 minutes. Thereaction solution was ice-cooled, this was added to a solution ofCompound 2 (6-bromo-nicotinaldehyde) (1.86 g) dissolved in a 28% aqueousammonia solution (20 mL) and methanol (60 mL) under ice-cooling, and themixture was stirred overnight while the temperature was graduallyelevated to room temperature. After the reaction solution wasconcentrated under reduced pressure, water and ethyl acetate were addedto carry out a liquid separation, the organic layer was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. Diethyl ether was added to the obtained solid residue,the mixture was triturated and solid was collected by filtration anddried to obtain Compound 3(2-bromo-5-[5-(trifluoromethyl)-1H-imidazole-2-yl]pyridine) (1.25 g).

MS (m/z): 292/294 [M+H]⁺

(2) To a solution of Compound 3(2-bromo-5-[5-(trifluoromethyl)-1H-imidazole-2-yl]pyridine) (13.65 g)dissolved in N,N-dimethylformamide (150 mL) was added a 60% sodiumhydride (2.62 g) under a nitrogen atmosphere under ice-cooling, and themixture was stirred for 30 minutes. To this was added2-(trimethylsilyl)ethoxymethyl chloride (12.4 mL) under ice cooling, andthe mixture was stirred overnight while the temperature graduallybrought back to room temperature. To the reaction solution was added asaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and the aqueous layer thus obtained was extracted withethyl acetate. The organic layers were combined, dried and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate) to obtain Compound 4(2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-yl]pyridine)(9.42 g).

MS (m/z): 422/424 [M+H]⁺

Reference Examples 13-2 to 13-3

A treatment was carried out in a manner similar to Reference Example13-1 to obtain compounds of Reference Examples 13-2 to 13-3 in Table 29below.

TABLE 29 Reference MS Example Starting material 1 Starting material 2Product (m/z) 13-2

422/424 [M + H]⁺ 13-3

421/423 [M + H]⁺

Reference Example 14

A treatment was carried out in a manner similar to the Example 11 (1)using Compound 1 (1.0 g) to obtain Compound 2 (2.68 g).

MS (m/z): 382/384 [M+H]⁺

Reference Example 15-1

(1) Compound 1 (5.9 g) was dissolved in ethanol (70 mL), and an 8Maqueous sodium hydroxide solution (25 mL) was added, and the mixture wasstirred at 70° C. for 19 hours. The reaction solution was concentratedunder reduced pressure, and ethyl acetate and water were added to theobtained residue to carry out a liquid separation. The aqueous layer wasseparated, and to this was added a 6M hydrochloric acid to adjust the pHto 5-6. Further, after neutralization by addition of phosphate buffer(pH 7.0), the mixture was extracted with a mixed solvent of ethylacetate and tetrahydrofuran. The organic layer was separated, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Tothe obtained residue was added diethyl ether, and the deposited solidwas collected by filtration to obtain Compound 2 (2.56 g).

MS (m/z): 268/270 [M+H]⁺

(2) Compound 2 (2.62 g), diisopropyl ethyl amine (2.21 mL) and benzylbromide (2.01 g) were added to N,N-dimethylacetamide (30 mL), and themixture was stirred at room temperature overnight. The reaction mixturewas ice-cooled, water (270 mL) was added, and the obtained solid wascollected by filtration and washed with n-hexane to obtain Compound 3(3.06 g).

MS (m/z): 358/360 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 6 (2)using Compound 3 (2.88 g) to obtain Compound 4 (1.76 g).

MS (m/z): 488/490 [M+H]⁺

Reference Example 15-2

A treatment was carried out in a manner similar to Reference Example15-1 to obtain a compound of Reference Example 15-2 in Table 30 below.

TABLE 30 Reference MS Example Intermediate Product (m/z) 15-2

487/489 [M + H]⁺

Reference Example 16

(1) To a solution of sodium methylate (1.39 g) in methanol (28.9 mL) wasadded Compound 1 (6-chloronicotinonitrile) (10 g), and the mixture wasstirred at 40° C. for 30 minutes. The reaction solution was concentratedunder reduced pressure, to the obtained residue was addedtetrahydrofuran (30 mL) to be mixed, and the mixture was concentratedunder reduced pressure. To the residue was added tetrahydrofuran (100mL), glycine methyl ester hydrochloride (9.06 g) and triethylamine(11.07 mL) were added, and the mixture was stirred at 55° C. for 6.5hours. The deposited solid was collected by filtration, washed withethyl acetate and dried to obtain Compound 2 (19.05 g).

MS (m/z): 196/198 [M+H]⁺

(2) Compound 2 (19.05 g) was heated in phosphorous oxychloride (45.4 mL)at reflux for 1.5 hours. The insoluble matter was filtered, and thefiltrate was neutralized by addition of a ethyl acetate and a 2N aqueoussodium hydroxide solution. Tetrahydrofuran and activated charcoal wereadded, the mixture was stirred and filtered thought Celite, and waterand ethyl acetate were added to the filtrate to carry out a liquidseparation. The organic layer was separated, washed with brine, anddried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure. To the obtained solid was added acetonitrile,and the solid was collected by filtration and dried to obtain Compound 3(4.87 g).

MS (m/z): 214/216 [M+H]⁺

(3) A treatment was carried out in a manner similar to the Example 6 (2)using Compound 3 (5.09 g) to obtain Compound 4 (5.96 g).

MS (m/z): 344/346 [M+H]⁺

Reference Example 17-1

(1) Palladium acetate (924 mg) and2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-PHOS)(5.88 g) were added to a mixed solvent of 1,4-dioxane (500 mL) and water(297 μL) under a nitrogen atmosphere, and the mixture was stirred at 80°C. for 10 minutes. After the reaction solution was cooled to roomtemperature, a separately prepared solution of Compound 1 (50.00 g),Compound 2 (45.97 g) and cesium carbonate (100.52 g) in 1,4-dioxane (500mL) was added, and the mixture was stirred at 100° C. for 4 hours. Thereaction solution was cooled and subsequently filtered through Celite,and Celite was washed with ethyl acetate. The obtained filtrate waswashed with water and then saturated brine, and dried over anhydroussodium sulfate. Subsequently, the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 80:20) to obtainCompound 3 (69.14 g).

MS (m/z): 349 [M+H]⁺

(2) Compound 3 (186.80 g) was dissolved in tetrahydrofuran (525 mL), andthe solution was ice-cooled. A 4N hydrochloric acid-1,4-dioxane solution(656 mL) was slowly added, and the mixture was stirred at roomtemperature overnight. The reaction solution was concentrated underreduced pressure, the obtained residue was crystallized after additionof t-butyl methyl ether, and the crystals were collected by filtration.The obtained crystals were suspended in ethyl acetate, a 2M aqueoussodium hydroxide solution was added to adjust the pH to 9, and themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and subsequently the solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=80:20 to0:100) to obtain Compound 4 (129.64 g).

MS (m/z): 249 [M+H]⁺

(3) Compound 4 (3.32 g), Compound 5 (2.36 g) and potassium carbonate(2.35 g) were added to dimethylsulfoxide (50 mL), and the mixture wasstirred at 100° C. for 2 hours. After the mixture was cooled to roomtemperature, ethyl acetate and water were added to carry out a liquidseparation. The organic layer was separated, washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=80:20 to0:100). The purified product was triturated in diethyl ether andcollected by filtration to obtain Compound 6 (3.24 g).

MS (m/z): 351 [M+H]⁺

Reference Example 17-2

A treatment was carried out in a manner similar to Reference Example17-1 to obtain a compound of Reference Example 17-2 in Table 31 below.

TABLE 31 Reference MS Example Starting material 1 Starting material 2Product (m/z) 17-2

318 [M + H]⁺

Reference Example 18

(1) A treatment was carried out in a manner similar to Reference Example7-1) using Compound 1 (7.08 g) and Compound 2 (2.5 g) to obtain Compound3 (2.78 g).

MS (m/z): 350 [M+H]⁺

(2) Compound 3 (2.78 g) was dissolved in 1,4-dioxane (10 mL), and a 4Nhydrogen chloride-1,4-dioxane solution (20 mL) was added under icecooling. The reaction solution was stirred at room temperatureovernight, and diethyl ether was added. The deposited solid wascollected by filtration, washed with diethyl ether and then dried toobtain Compound 4 (2.27 g).

MS (m/z): 250 [M+H]⁺

(3) Compound 4 (600 mg), Compound 5 (500 mg), potassium carbonate (871mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (345 μL) were added to1,4-dioxane (15 mL), and the mixture was stirred at 99° C. for two days.After the reaction solution was concentrated under reduced pressure,ethyl acetate and water were added to carry out a liquid separation. Theorganic layer was separated, washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=100:0 to 70:30). To the obtainedsolid were added ethyl acetate and n-hexane under ice cooling, and thedeposit was collected by filtration to obtain Compound 6 (515 mg).

MS (m/z): 352 [M+H]⁺

Reference Example 19

(1) A treatment was carried out in a manner similar to Reference Example7-1 (1) using Compound 1 (7.64 g) and Compound 2 (5.0 g) to obtainCompound 3 (8.27 g).

MS (m/z): 210 [M+H]⁺

(2) Compound 3 (3.0 g) was dissolved in diethyl ether (20 mL), benzylbromide (3.4 mL) was added, and the mixture was stirred at roomtemperature for two days. Subsequently, the deposited solid wascollected by filtration. The solid was dissolved in methanol (60 mL),sodium borohydride (2.17 g) was added portionwise, and the mixture wasstirred at room temperature for 2 hours. After a saturated aqueousammonium chloride solution and methylene chloride were added to carryout a liquid separation, the organic layer was separated, washed withsaturated brine, and concentrated under reduced pressure. The obtainedresidue was dissolved in methanol (60 mL), a 10% palladium-carbon (300mg) was added, and the mixture was stirred under a hydrogen atmospherefor 7 hours. The 10% palladium-carbon was filtered out and the filtratewas concentrated under reduced pressure. The residue was dissolved inacetic acid (50 mL), a 10% palladium-carbon (300 mg) was added, and themixture was stirred under a hydrogen atmosphere at 70° C. for 7 hours.The 10% palladium-carbon was filtered out, the filtrate was concentratedunder reduced pressure, and the obtained residue was purified byNH-silica gel column chromatography (chloroform:methanol=100:0 to 98:2)to obtain Compound 4 (1.34 g).

MS (m/z): 216 [M+H]⁺

Reference Example 20-1

A treatment was carried out in a manner similar to Reference Example 7-1(4) and Reference Example 7-1 (5) using Compound 1 (514 mg) to obtainCompound 2 (416 mg) as an acetate salt.

MS (m/z): 369 [M+H]⁺

Reference Examples 20-2 to 20-3

A treatment was carried out in a manner similar to Reference Example20-1 to obtain compounds of Reference Examples 20-2 and 20-3 in Table 32below.

TABLE 32 Reference MS Example Intermediate Product (m/z) 20-2

368 [M + H]⁺ 20-3

335 [M + H]⁺

Reference Example 21-1

(1) Compound 1 (4-bromophenol) (61.0 g), Compound 2 (methylhydroxypivalate) (69.9 g) and triphenylphosphine (138.7 g) weredissolved in tetrahydrofuran (350 mL), and the mixture was cooled to 0°C. under a nitrogen atmosphere. Subsequently, a 40% diethylazodicarboxylate-toluene solution (240 mL) was added dropwise, and themixture was stirred while the temperature brought back to roomtemperature and then at 80° C. overnight. After the temperature of thereaction solution was brought back to room temperature, the reactionsolution was concentrated under reduced pressure, and to the obtainedresidue was added diethyl ether (500 mL). The obtained solid wasfiltered and washed with diethyl ether. The filtrate was concentratedunder reduced pressure and the obtained residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=100:0, 19:1 and to9:1) to obtain Compound 3 (102.2 g).

MS (m/z): 304/306 [M+NH₄]⁺

(2) Compound 3 (102.2 g), bis(pinacolato)diboron (98.5 g), a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (7.73 g), 1,1′-bis(diphenylphosphino)ferrocene(5.86 g) and potassium acetate (103.8 g) were dissolved in 1,4-dioxane(470 mL), and the mixture was stirred under a nitrogen atmosphere at 80°C. overnight. After the temperature of the mixture was brought back toroom temperature, the mixture was concentrated under reduced pressure,and ethyl acetate and water were added to the obtained residue to carryout a liquid separation. The organic layer was separated, washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=100:0, 9:1 and to 4:1), and to the obtained residue was addedn-hexane, and the mixture was stirred under ice-cooling for 1 hour. Thesolid was collected by filtration and dried to obtain Compound 4 (95.5g).

MS (m/z): 335 [M+H]⁺

Reference Examples 21-2 to 21-9

A reaction was carried out in a manner similar to Reference Example 21-1using the following raw materials 1 and 2 to obtain compounds ofReference Examples 21-2 to 21-9 in Table 33 below.

TABLE 33 Reference MS Example Raw Material 1 Raw Material 2 Product 4(m/z) 21-2

336 [M + H]⁺ 21-3

350 [M + H]⁺ 21-4

350 [M + H]⁺ 21-5

348 [M + H]⁺ 21-6

362 [M + H]⁺ 21-7

404 [M + H]⁺ 21-8

420 [M + H]⁺ 21-9

424 [M + H]⁺

Reference Example 22-1

(1) To a solution of dimethyl 1,1-cyclohexanedicarboxylate (2.08 g) inmethanol (15 mL) was added a 1N aqueous sodium hydroxide solution (13.2mL), and the mixture was stirred at room temperature for 23 hours. Themethanol was distilled off under reduced pressure, and the residue waswashed with n-hexane. To an aqueous layer was added 1N hydrochloric acid(10 mL), and the mixture was extracted with chloroform. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.After drying, concentration under reduced pressure provided Compound 2(1.58 g) as a colorless oil.(2) A solution of Compound 2 (1.57 g) in tetrahydrofuran (15 mL) wasice-cooled under a nitrogen stream, and a 1M solution of aborane/tetrahydrofuran complex in tetrahydrofuran (12 mL) was addeddropwise. After dropwise addition, the reaction solution was stirred atroom temperature for 1.5 hours. The reaction solution was ice-cooled,and methanol was added. After the mixture was concentrated under reducedpressure, the residue was dissolved in methanol (15 mL), 20%hydrochloric acid/methanol (4 mL) was added, and the mixture was stirredat 70° C. for 18 hours. The reaction solution was concentrated underreduced pressure, to the residue was added an aqueous saturated sodiumbicarbonate solution, and the mixture was extracted with chloroform. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. To this was added NH silica gel, and the mixture wasstood. The mixture was filtered and concentrated under reduced pressureto obtain Compound 3 (1.14 g) as a colorless oil.

MS (m/z): 131 [M+H]⁺

Reference Example 22-2

(1) To a solution of dibenzyl malonate (25 g) in N,N-dimethylformamide(250 mL) were added potassium carbonate (121.5 g) and dibromoethane(22.7 mL), and the mixture was stirred at room temperature overnight. Tothe reaction solution was added water, and the mixture was extractedwith ethyl acetate. The extract was washed with water, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10 to 80:20) to obtain Compound 2 (25.33 g)as a colorless oil.(2) A solution of Compound 2 (16.9 g) in methylene chloride (338 mL) wascooled to −65° C. or lower, and a 1M diisobutylaluminum hydride/toluenesolution (119.8 mL) was added dropwise. After dropwise addition, thetemperature of the reaction solution was elevated to −15° C. over 30minutes. To the reaction solution were added a saturated aqueous ammoniachloride solution (170 mL) and 1N hydrochloric acid (170 mL), and themixture was stirred for 10 minutes. To the obtained gel-like mixture wasadded further 1N hydrochloric acid (300 mL) to dissolve the mixture. Theorganic layer was separated, washed with saturated sodium bicarbonatewater, and dried over anhydrous sodium sulfate. After concentrationunder reduced pressure, the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=90:10 to 50:50) to obtainCompound 3 (5.18 g) as a colorless oil.

MS (m/z): 207 [M+H]⁺

Reference Example 22-3

(1) To a solution of dimethyl diethylmalonate (25 g) in methanol (250mL) was added a 1N aqueous sodium hydroxide solution (132.8 mL), and themixture was stirred at room temperature overnight. The methanol wasdistilled off under reduced pressure, and the residue was washed withmethylene chloride. To the aqueous layer was added 1N hydrochloric acidto adjust the pH to 3, and the mixture was extracted with diethyl ether.The extract was washed with water, dried over anhydrous magnesiumsulfate. After drying, concentration under reduced pressure providedCompound 2 (23.1 g) as a colorless oil.(2) Anhydrous magnesium sulfate (63.85 g) was suspended in methylenechloride (230 mL), concentrated sulfuric acid (7.07 mL) was addeddropwise at room temperature, and the mixture was stirred for 15minutes. To this was added a solution of Compound 2 (23.1 g) inmethylene chloride (115 mL), and then tert-butanol (63.5 mL) was added.The reaction solution was stirred at room temperature overnight. Thereaction mixture was filtered, and the filtrate was ice-cooled andrendered alkaline with an aqueous saturated sodium hydrogen carbonatesolution. The organic layer was separated, washed with saturated brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain Compound 3 (26.09 g) as a colorless oil.(3) To a solution of the obtained Compound 3 (14 g) in tetrahydrofuran(140 mL) was added dropwise a 1M solution of lithiumtri(tert-butoxy)aluminum hydride in tetrahydrofuran (150 mL) at roomtemperature, and the mixture was gradually heated and then at reflux for8 hours. The reaction solution was ice-cooled, and 1N hydrochloric acid(500 mL) was added dropwise. The reaction mixture was extracted withdiethyl ether, and the extract was washed with water and an aqueoussaturated sodium bicarbonate solution, and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=90:10 to 80:20) to obtain Compound 4 (7.41 g) as a colorlessoil.

¹H NMR (DMSO-d₆, 400 MHz) (ppm): δ 4.48 (t, J=5.2 Hz, 1H), 3.42 (d,J=5.1 Hz, 2H), 1.46 (m, 4H), 1.38 (s, 9H), 0.74 (t, J=7.2 Hz, 6H)

Reference Example 22-4

(1) To a solution of diethyl 1,1-cyclobutanedicarboxylate (25 g) inethanol (250 mL) was added a 1N aqueous sodium hydroxide solution (125mL), and the mixture was stirred at room temperature for 6 days. Theethanol was distilled off under reduced pressure, and the residue waswashed with diethyl ether. To the aqueous layer was added 1Nhydrochloric acid to adjust the pH to 3, and the mixture was extractedwith chloroform. The extract was washed with water, dried over anhydrousmagnesium sulfate. After drying, concentration under reduced pressureprovided Compound 2 (20.67 g) as a colorless oil.(2) Anhydrous magnesium sulfate (52 g) was suspended in methylenechloride (186 mL), concentrated sulfuric acid (5.8 mL) was addeddropwise at room temperature, and the mixture was stirred for 15minutes. To this was added a solution of Compound 2 (18.6 g) inmethylene chloride (93 mL), and then tert-butanol (52 mL) was added. Thereaction solution was stirred at room temperature overnight. Thereaction mixture was filtered, and the filtrate was ice-cooled andrendered alkaline with an aqueous saturated sodium bicarbonate solution.The organic layer was separated, washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure toobtain Compound 3 (24.7 g) as a colorless oil.(3) To a solution of the obtained Compound 3 (15.9 g) in tetrahydrofuran(160 mL) was added dropwise a 1M solution of lithiumtri(tert-butoxy)aluminum hydride (153 mL) in tetrahydrofuran at roomtemperature, and the mixture was gradually heated and then at reflux for3.5 hours. The reaction solution was ice-cooled, a saturated aqueousammonium chloride solution was added, and the mixture was stirred atroom temperature. The obtained gel-like mixture was filtered, andconcentrated under reduced pressure. Subsequently, the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=100:0 to 75:25) to obtain Compound 4 (11.02 g) as a colorlessoil.

MS (m/z): 187 [M+H]⁺

(4) To a solution of Compound 4 (3 g) in methanol (60 mL) was added 2Nhydrochloric acid/methanol (6 mL), and the mixture was heated at refluxfor 5.5 hours. The reaction solution was diluted with methylenechloride, washed with an aqueous saturated sodium bicarbonate solutionand saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain Compound 5 (2.16 g) as acolorless oil.

MS (m/z): 149 [M+H]⁺

Experimental Example 1 DGAT1 Inhibitory Activity Experimental Method

(1) Cloning of Human DGAT1 Gene and Preparation of RecombinantBaculovirus

Human DGAT1 gene was obtained by using a human cDNA library as a temple,and amplifying the base sequence (245-1711 in Genbank Accession No.NM_012079) which codes DGAT1 by PCR reaction.

Thus obtained human DGAT1 gene was ligated into a plasmid, pVL1392 (BDBiosciences) to prepare an expression plasmid, pVL1392-DGAT1. Further, arecombinant baculovirus was prepared by using BD BaculoGold BaculovirusExpression vector system (BD Biosciences).

(2) Preparation of Microsome of Human DGAT 1 Enzyme HighlyExpressed-Insect Cell

The preparation of human DGAT 1 enzyme was carried out by infecting therecombinant baculovirus obtained in the previous item with expresSF+®insect cell (Nosan Corporation). After the recombinant baculovirus wasadded to the expresSF+® cell and the mixture was cultivated for 72hours, the cells were collected by centrifugation, and freeze-preservedat −80° C. The freeze-preserved cells were fused in an ice water,suspended in a buffer (200 mM Sucrose, 1 mM EDTA, 100 mM Tris-HCl(pH7.4)) to which Complete Protease Inhibitor (Roche) had been added,and subjected to a sonication. Then, a microsome fraction was obtainedby an ordinary method and freeze-preserved at −80° C. as a highlyDGAT1-expressing microsome.

(3) Measurement of DGAT1 Inhibitory Activity

As a buffer used for the enzymatic reaction of DGAT1, 100 mM Tris-HCl(pH7.4), 200 mM Sucrose, and 20 mM MgCl₂, 0.125% Bovin Serum Albumin(BSA) were used. To this buffer, a test compound with predeterminedconcentration of test compound, 15 μM dioleoylglycerol, 5 μM[¹⁴C]-palmitoyl-CoA, 100 μg-protein/mL, highly DGAT1-expressingexpresSF+® microsome, 0.75% acetone, and 1% dimethylsulfoxide wereadded, and a triglyceride (TG) synthesis reaction in a volume of 100 μLwas carried out at 30° C. for 20 minutes. 90 μL of the reaction solutionwas added to 810 μL of methanol to cease the reaction. The reactionsolution was added to Oasis® μ Elution plate (Waters) and eluted with150 μL of mixture of acetonitrile:isopropanol (=2:3). 150 μL ofMicroScinti™-40 (Perkin-Elmer Corp.) were added to the eluted solutionand the mixture was sufficiently stirred, and an amount of [¹⁴C]-TGproduced in the reaction was determined by measuring using TopCount™-NXT(Perkin-Elmer Corp.).

The inhibitory ratio was calculated by the following equation.Inhibitory ratio (%)=(1−(TG amount when the test compound wasadded−blank TG amount)/(control TG amount−blank TG amount))×100

Here, a count of [¹⁴C]-TG in the solution where the reaction was carriedout without adding the test compound was regarded “control TG amount”,and a count of [¹⁴C]-TG in the solution to which the test compound andhighly DGAT1 expressing expresSF+® microsome were not added was regardedas “blank TG amount”. Further, a concentration of test compound requiredto inhibit the synthesis of [¹⁴C]-TG by 50% (IC₅₀ value) was calculatedby Prism 5.01 (GraphPad Softwear).

Experimental Result

The experimental results are shown in Table 34 as below.

TABLE 34 Example IC₅₀ (nM) Example IC₅₀ (nM) 1-1 8.0 1-3 6.9  1-17 11 1-28 16.9  1-31 26.6  1-34 2.1  1-35 13  1-37 11  1-44 4.2  1-58 11 1-63 3.3  1-68 19 2-7 2.5 2-8 2.9  2-11 3.7  2-16 5.7 3-7 2.5 4-1 1.74-3 2.1  4-15 0.94 5-2 3.2 6 9.1  7 11 8 6.1  9 7.9 10 6.4 11 44.4 124.7 14 3.2 17 2.9 21-2  6.9 23-1  3.3 24-2  26 25 36 29-3  15 30 2931-2  6.8 32-2  1.7 34 8.8 35-1  2.7 37-3  4.3 37-4  14 37-6  21 38-5 20 39 16 40-1, Compound 4 12 42 24 43-1  8.5 43-2  16 43-3  16 43-7  1744-6  0.78 44-11 25 45-1  1.5 46-1  9.0 46-4  4.4 46-5  1.2 47-1  9.0 488.2 49 17 51 15 52 21 55 8.1 57 76 59 2.6 60 18 61 5.2 67 3.9 108  5.0109 12 110  1.1 72 2.2 75 1.1 74 1.1 77 28 78 1.7 80 3.3 82 4.6 83 1.8104 6.8

Experimental Example 2 Triglyceride (TG) Elevation-Suppressing Action inPlasma by Lipid Administration Experimental Method

Male ICR mice, 6 to 9 weeks old, were fasted overnight, and a testcompound was suspended in 0.2% carboxymethylcellulose solution and thesuspension was orally administered. After 30 minutes, lipid (Intralipos,20%, Otsuka Pharmaceutical, 10 mL/kg) was orally administered. Blood wassampled through the caudal vein immediately before and 2 hours after theadministration of the lipid to obtain plasma. TG in the plasma wasdetermined by using Triglyceride E-Test Wako (Wako Pure Chemical), andthe elevation value of TG in the plasma by the lipid administration wascalculated. By using the plasma TG elevation value in the solventcontrol group as the control, the plasma TG elevation-suppressing ratiowas calculated in the test compound administrating group.

Experimental Result

As a result as the above, the test compound of the example showed theplasma TG elevation-suppressing ratio at the dose of 5 mg/kg as shown inTable 35 as below.

TABLE 35 Plasma TG elevation Plasma TG elevation suppressing ratiosuppressing ratio Example (5 mg/kg) Example (5 mg/kg)  1-58 66%  2-1162%  4-1 74%  7 47% 10 53% 31-2 74% 32-2 63% 37-3 64% 37-4 69% 43-1 66%43-2 66% 46-5 59% 48 61% 51 49.3%   52 70.8%   59 72.0%   61 77.4%   6756.8%   110  73.0%   75 74.6%   74 67.5%   78 73.8%   82 67.9%   8379.5%  

Experimental Example 3 Food Intake-Suppressing Action ExperimentalMethod

Male C57BL/6J mice, 7 to 10 weeks old, were fasted overnight, and a testcompound was suspended in 0.2% carboxymethylcellulose solution and thesuspension was orally administered. Immediately, the animals were givenhigh fat diet (Oriental Yeast, 60 cal % fat) and allowed to take freely.The food intake for 4 hours was determined, and the decrease ratio ofthe food intake (food intake-suppressing ratio) was calculated in thetest compound administrating group, relative to the food intake in thesolvent control group as a control.

Experimental Result

The test compound of the example showed the food intake-suppressingratio at the dose of 5 mg/kg as shown in Table 36 as below.

TABLE 36 Food intake- suppressing Food intake- ratio suppressing ratioExample (5 mg/kg) Example (5 mg/kg)  1-58 68%  2-11 55%  4-1 79%  7 73%10 67% 31-2 74% 32-2 65% 37-3 69% 37-4 82% 43-1 40% 43-2 82% 46-5 54% 4864% 51 65% 52 75% 59 73% 61 60% 67 50% 110  68% 75 70% 74 82% 78 44% 8260% 83 59%

Experiment Example 4 Body Weight Gain-Suppressing Action, HypoglycemicAction and Plasma Insulin-Decreasing Action in KK-Ay Mouse ExperimentalMethod

Male KK-Ay mice, 8 weeks old, were given high fat diet (Oriental Yeast,60 cal % fat), the test compound was suspended in 0.2%carboxymethylcellulose solution and the suspension was orallyadministered once a day. After the oral administration was repeated for2 weeks, the body weight gain-suppressing ratio of the test compound wascalculated, relative to the body weight gain of the solvent controlgroup during the test period as 100%. After the final administration,the animals were fasted overnight, and blood was sampled through thecaudal vein. The blood sugar and the insulin in the plasma weredetermined by using Glucose C II-Test Wako (Wako Pure Chemical) andMouse Insulin Measurement Kit (Morinaga Institute of BiologicalScience), respectively.

Experimental Result

As a result as above, the test compound of the example showed thehypoglycemic action, the plasma insulin-decreasing action, and the bodyweight gain-suppressing action at the dose of 30 mg/kg/day as shown inTable 37 as below, relative to the solvent control group.

TABLE 37 Hypoglycemic Plasma insulin- Body weight gain- actiondecreasing action suppressing action Example (30 mg/kg/day) (30mg/kg/day) (30 mg/kg/day)  7 42% 34% 34% 10 37% 40% 32% 31-2 55% 45% 41%43-1 36% 53% 21% 51 26% 21% 41% 61 44% 50% 36% 67 47% 14% 43% 74 32% 29%41% 78 57% 69% 56%

INDUSTRIAL APPLICABILITY

The continuation aromatic cyclic compound of the present invention or apharmaceutically acceptable salt thereof has an excellent DGAT1inhibitory action and can be used as a prevention/treatment agent ofobesity.

The invention claimed is:
 1. The compound represented by the generalformula (1-B):

wherein ring A represents pyridine which may be substituted with 1 to 3alkyl; ring B² represents pyridine which may be substituted with 1 to 3substituent groups which are halogen atoms or cyano; R^(2b) representsalkyl which may be substituted with 1 to 6 halogen atoms, alkoxy whichmay be substituted with 1 to 6 halogen atoms, alkylthio, an aromatichydrocarbon group which may be substituted with 1 to 3 alkoxy,cycloalkyl which may be substituted with 1 to 7 halogen atoms, aryloxywhich may be substituted with halogen atom or cyano, cycloalkyloxy, orcycloalkylalkoxy; X represents a single bond or —O—; Y^(b) representsalkyl which may be substituted with carboxy or cycloalkyl which may besubstituted with 1 to 3 substituent groups which are carboxyalkyl,carboxy, alkoxyalkyl or aminocarbonyl; or a pharmaceutically acceptablesalt thereof; wherein when 2 or more substituent groups are present, thesubstituent groups may be the same or different.
 2. The compoundaccording to claim 1 wherein R^(2b) is alkyl which may be substituted,alkoxy which may be substituted, an aromatic hydrocarbon group which maybe substituted, or aryloxy which may be substituted, or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1 wherein X is —O—, and Y^(b) is alkyl which may be substitutedwith carboxy, or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 1 which is selected from2,2-dimethyl-3-({4′-methyl-5-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]-2,3′-bipyridin-6′-yl}oxy)propanoicacid, and2,2-dimethyl-3-({4-methyl-6′-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]-3,3′-bipyridin-6-yl}oxy)propanoicacid, or a pharmaceutically acceptable salt thereof.
 5. A diacylglycerolacyltransferase (DGAT) 1 inhibitor composition comprising the compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof asactive ingredient, and a pharmaceutically acceptable carrier.